MATERIALS AND METHODS FOR DETERMINING SENSITIVITY POTENTIAL OF COMPOUNDS

Abstract

The invention concerns in vitro proteomic analysis of cells to determine the sensitizing potential (including allergic potential) of compounds on said cells. Several protein markers are provided that allow assays to be performed to determine whether a chemical has a sensitizing potential of contact sensitizers.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to in vitro proteomic analysis of cells to determine the sensitizing potential (including allergic potential) of compounds on said cells. Several protein markers have been identified which allow cellular based analysis to determine whether a compound has allergic or irritant potential. Particularly, but not exclusively, the invention provides assays for determining whether a test chemical has sensitizing potential of contact, i.e. on skin.

BACKGROUND OF THE INVENTION

[0002] Allergy is a type 1 hypersensitive disorder of the immune system. Common allergic reactions include asthma and contact dermatitis. Worldwide the occurrence of allergic diseases is steadily increasing. Allergic disorders have a negative impact on a patient's professional and social life. The costs to the healthcare systems of treating allergic diseases are substantial and increase with the corresponding rise in prevalence. Allergic contact dermatitis (ACD) is accepted to be the most prevalent form of immunotoxicity found in humans. ACD is a T cell mediated delayed skin hypersensitivity which develops after repeated exposure to common metals and a variety of different chemicals and cosmetics. Common chemical contact sensitizers are cinnamaldehyde (CA), dinitrochlorobenzene (DNCB), glyoxal, eugenol, p-phenylenediamine (PPD), and tetramethylthiuram (TMTD). PPD is a chemical substance that is widely used as a permanent hair dye, in textiles, temporary tattoos, photographic developer, printing inks, black rubber, oils, greases and gasoline.

[0003] Many occupational allergens causing allergic contact dermatitis are chemicals (or haptens) that have to bind to a carrier protein to trigger a delayed immune response.

[0004] Currently, the sensitizing potential of a chemical is assessed in animal experiments such as the guinea pig maximization test (Magnussen and Kligman, 1969) and the local lymph node assay (LLMA) (Kimber et al. 1995). However, the European Directive 86/609/EEC and the 7th Amendment to the Cosmetics Directive enforce an animal testing ban for all cosmetic ingredients since March 2009. Moreover, a marketing ban is in force for cosmetic products containing ingredients tested in animals for all endpoints except repeated dose toxicity, for which the deadline is 2013.

[0005] Much research has been devoted to the development of in vitro and in silico predictive testing methods. However, validated in vitro assays for identification and screening of contact sensitizing chemicals are not available.

[0006] Chemical allergens are typically small with masses under 1000 daltons, are electrophilic or hydrophilic and can react with nucleophilic amino acids of proteins. Such reactive low molecular weight chemicals can become allergenic when they bind to larger carrier proteins in the body to form hapten-protein conjugates. Some chemical allergens are not inherently allergenic and must undergo metabolic transformation (pro-hapten) or oxidation (pre-hapten) before participating in an allergic response. For example eugenol is considered a pro-hapten, whereas isoeugenol and PPD are classified as pre-haptens.

[0007] The skin is the largest organ of the human body and represents a large contact site for potential allergy inducing chemicals. It consists of Langerhans cells (LCs, antigen-presenting dendritic cells), T-lymphocytes, natural killer cells and keratinocytes actively participating in an allergic response. About 95% of all epidermal cells are keratinocytes and are the first cells to encounter foreign antigens. During the induction phase of ACD a chemical allergen binds to an epidermal protein to form a hapten-carrier protein complex. As keratinocytes also express drug metabolizing enzymes they also participate in the conversion of pro-drugs to sensitizers. Upon contact with a chemical hapten keratinocytes produce a number of cytokines such as interleukin-18 (IL-18) and tumour necrosis factor alpha (TNF-alpha) inducing migration of LCs to local lymph nodes. Hapten-protein conjugates are recognized by dendritic cells (DCs) which internalize process and transport antigen to the lymph node and present it to T-lymphocytes.

[0008] After uptake and processing of foreign or self antigens in peripheral tissues, LCs undergo a complex maturation process. Therefore, such test systems comprising primary keratinocytes, human immortalised keratinocytes (HaCaT), human keratinocyte cell lines such as NCTC 2544, epithelial cells or human reconstructed epidermal models such as EpiDerm (MatTek Corporation USA) or EpiSkin ((SkinEthic, France) could be useful to develop alternative approaches for predicting the sensitizing potential of chemicals.

[0009] The cellular response to irritants and allergens is manifested in two principal ways. Initial exposure is likely to trigger altered gene expression which is subsequently followed by changes in the protein composition of the exposed cells. It is to be appreciated that potential markers of irritant or allergic exposure may be found through the analysis of gene expression or by proteomic analysis of model systems. It is the primary objective of the present invention to provide protein markers whose expression is known to increase or decrease in cells exposed to different classes of chemical compounds. The skilled person would understand that changes in protein levels may also be accompanied, and are often preceded by a parallel change in gene expression and such gene expression changes are within the scope of the present invention.

[0010] Whilst there have been very few studies on protein expression changes in model systems for chemical safety testing, there have been several studies on the effects of irritants and allergens on gene expression profiles:

[0011] Previous studies have focused on developing in vitro sensitization assays based on measuring cytokine mRNA expression and production in murine and human keratinocyte cell lines (Corsini et al. 2009; Van Och et al. 2005). For example the human keratinocyte cell line NCTC2544 responds to application of contact sensitizers with production of interleukin-18 (IL-18). In contrast, irritant and respiratory sensitizers failed to increase IL-18 production (Corsini et al. 2009).

[0012] Others have focused on measuring the activation of a cellular toxicity pathway that recognizes various electrophilic chemicals. This pathway comprises the cellular sensor protein Kelch-like ECH-associated protein (Keap1) and the transcription factor Nrf2, which binds to the antioxidant response element (ARE) in the promoter of phase 2 detoxification genes (Natsch and Emter 2008; Natsch 2010). Activation of the Keap2/Nrf2 pathway has been utilized by Givaudan Fragance Research (Duebendorf, Switzerland) to develop the human KeratinoSens assay which is based on expressing the luciferase gene under the control of the ARE of the AKR1C2 gene in HaCaT keratinocytes (Emter et al. 2010). After incubation with a test chemical induction of luciferase activation and cytotoxicity are measured to identify skin sensitizers. The KeratinoSens assay was used to screen 43 sensitizers, and 24 non-sensitizers. The system correctly identified 38 sensitizer and 19 non-sensitizer. Among the false negative sensitizer was phenyl benzoate which reacts with Lysine residue a reaction which is not identified by ARE-based assays (Natsch et al. 2010; Emter et al. 2010). This means that additional biomarker from other pathways are needed to identify a full spectrum of chemical allergens.

[0013] Yoshikawa et al. (2010) described the use of two strains of human keratinocytes, bulge-derived keratinocytes (BDKs), human neonatal epidermal keratinocytes (NHEKs), and the human monocytic leukemia cell line THP-1 to identify genes responding to incubation with chemical sensitizers. BDKs, NEHKs and THP-1 showed high reactivity to the chemical sensitizer DNCB with up-regulation of the Nrf2 pathway. However, great differences in the gene expression of potential biomarkers including interleukin 1B (IL1B), interleukin-8 (IL8) or inhibitor of DNA binding 2 (ID2) was observed between the three cell types. For example gene expression of IL1B and IL-8 was much higher induced by DNCB in BDKs compared to THP-1 cells. This means that different molecular pathways are induced in different cell types and different sets of biomarkers are needed in different cellular test systems.

[0014] Vandenbriel et al. (2010) analyzed changes in gene expressing in HaCaT cells using Affymetrix U133 Plus 2.0 Arrays exposed to eight known sensitizers and six irritants. Based on support vector machine (SVM) algorithms 13 most discriminating genes between sensitizer and irritants were selected and included genes from oxidative stress pathways and Keap1-dependent genes.

[0015] Accordingly, there is still no consensus as to the most appropriate cell lines or genes to use as surrogate screens for chemical safety in vitro.

SUMMARY OF THE INVENTION

[0016] Starting from the assumption that allergic responses will be mediated by changes in protein expression, the present inventors have carried out a detailed proteomic analysis of keratinocytes exposed to known irritants and sensitizers to reveal putative markers. Surprisingly, there was virtually no overlap between previously reported gene regulations and proteins seen to change in response to exposure with different classes of chemicals. As a result the inventors have defined a small panel of 102 proteins that can serve as objective measures of allergic and skin irritation response in in vitro screens of chemical safety.

[0017] The invention allows methods to be carried out for predicting the sensitizing potential of chemical sensitizers using in vitro methods capable of replacing whole organism testing, based on the measurement of any one or more of these protein markers.

[0018] Accordingly, at its most general, the present invention provides materials and methods for determining the sensitising potential of a test compound using in vitro proteomic analysis using one or more of the 102 protein markers identified in Table 1.

[0019] The sensitising potential of a compound includes its ability to cause an allergic reaction, or its ability to act as a non-allergenic irritant.

[0020] In a first aspect, there is provided an in vitro method for determining the sensitizing potential of a test compound, comprising the steps of

(a) contacting said test compound with a cell; (b) determining the presence or a change in the level of expression of one or more marker proteins selected from Table 1 in said cell; and (c) determining the sensitizing potential of said test compound based on said presence or change in level of expression wherein a change in the presence or level of expression of said one or more marker proteins is indicative of said test compound having sensitizing potential.

[0021] The presence or a change in level of expression may be determined by establishing the amount of protein marker in the cell or surrounding environment. Alternatively, it may be determined by detecting the presence or amount of nucleic acid sequence encoding said marker protein or form thereof, e.g. mRNA. The presence or increase in either encoding nucleic acid or the protein itself may be measured indirectly. For example, nucleic acid may be extracted from the cell and amplified before quantification. Protein may also be extracted from the cells and enriched and/or labelled prior to quantification.

[0022] Table 1 contains 102 protein markers. In preferred embodiments of the invention, the method determines the presence or a change in level of expression of a plurality of these protein markers. Thus, the method according to the first aspect of the invention may determine the presence or change in level of expression of 2, 3, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, or more protein markers provided in Table 1.

[0023] Alternatively, the method may comprises determining the presence or change in level of expression of at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% of the protein markers provided in Table 1.

[0024] The method according to this and other aspects of the invention may comprise comparing said presence of level of expression of the one or more protein markers with a reference level. In light of the present disclosure, the skilled person is readily able to determine a suitable reference level, e.g. by deriving a mean and range of values from cells derived from the same, or equivalent cell line. In certain embodiments, the method of this and other aspects of the invention may further comprise determining a reference level for one or more of said marker proteins, above which or below which the presence or amount of said one or more protein markers being expressed in the cell in contact with the test compound can be considered to indicate the sensitizing potential of the compound.

[0025] However, the reference level is preferably a pre-determined level, which may for example be provided in the form of an accessible data record.

[0026] The test compound may be contacted with any cell. Preferably, the cell is representative of a mammalian skin cell, e.g. a primary keratinocyte or keratinocyte derived cell lines. More preferably, the cell is obtained from a primary cell e.g. epidermal keratinocytes, bulge-derived keratinocytes or foreskin keratinocytes. In another embodiment the cell is derived from a human cell with keratinocytic properties. For example HaCaT cells can be purchased from CLS--Cell Lines Service (Eppelheim, Germany) and NCTC2544 can be purchased from ICLC (Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy).

[0027] Many other cells lines will be known to the skilled person.

[0028] The method according to this aspect of the invention may be used to determine the contact sensitizing potential of the test compound by determining the presence or a change in expression level of one or more marker proteins provided in Table 1 (A) group 1 when the test compound is contacted with the cell. The one or more marker proteins may be 2, 4, 5, 6, 8 or more selected from Table 1 (A) group 1; or may include all 12 marker proteins.

[0029] In a further embodiment, the method may be used to determine the irritating potential of a test compound by determining the presence or a change in expression level of one or more marker proteins provided in Table 1 (B) Group 2 when the test compound is contacted with the cell. The one or more marker proteins may be 2, 3 or more selected from Table 1 (B) Group 2, or may include all 6 marker proteins.

TABLE-US-00001 TABLE 1 Protein markers of chemical sensitizing effect Change of cell lysate protein SEQ IPI level on exposure ID Accession UniProt to known sensitizers No. Protein Name Number Gene name Accession or irritant* A Group 1 1 Glyceraldehyde-3-phosphate IPI00219018 GAPDH P04406 Increased dehydrogenase 2 Thioredoxin IPI00216298 TXN P10599 Increased 3 Isoform Beta of LIM domain IPI00008918 LIMA1 Q9UHB6 Increased and actin-binding protein 1 4 Isoform 1 of IPI00008752 MT1G P13640 Increased Metallothionein-1G 5 60S ribosomal protein L31 IPI00026302 RPL31 P62899 Increased 6 Annexin A3 IPI00024095 ANXA3 P12429 Increased 7 Eukaryotic translation IPI00016910 EIF3CL; Q99613 Increased initiation factor 3 subunit EIF3C C 8 Rho GDP-dissociation IPI00003815 ARHGDIA P52565 Decreased inhibitor 1 9 Poly(rC)-binding protein 1 IPI00016610 PCBP1 Q15365 Increased 10 Nucleosome assembly protein IPI00023860 NAP1L1 P55209 Increased l-like 1 11 Heat shock 70 kDa protein 1 IPI00304925 HSPA1B; P08107 Increased HSPA1A 12 Aldo-keto reductase family IPI00005668 AKR1C2 P52895 Increased 1 member C2 B Group 2 13 Ribosomal protein L14 IPI00555744 RPL14 P50914 Increased* variant 14 Epidermal growth factor IPI00290337 EPS8 Q12929 Increased* receptor kinase substrate 8 15 Plasminogen activator IPI00007117 SERPINB2 P05120 Increased* inhibitor 2 16 Isoform 1 of Voltage- IPI00031804 VDAC3 Q9Y277 Increased* dependent anion-selective channel protein 3 17 Annexin A1 IPI00218918 ANXA1 P04083 Increased* 18 Cystatin-B IPI00021828 CSTB P04080 Increased* C Group 3 19 Isoform 1 of Clathrin heavy IPI00024067 CLTC Q00610 Decreased chain 1 20 Elongation factor 1-alpha 1 IPI00396485 EEF1A1 P68104 Decreased 21 Annexin A2 isoform 1 IPI00418169 ANXA2 P07355 Increased 22 cDNA FLJ54535, highly IPI00910979 PKM2 B4DUU6 Increased similar to Pyruvate kinase isozymes 23 Isoform alpha-enolase of IPI00465248 ENO1 P06733 Increased Alpha-enolase 24 Neuroblast differentiation- IPI00021812 AHNAK Q09666 Increased associated protein AHNAK 25 Isoform 1 of Heat shock IPI00003865 HSPA8 P11142 Decreased cognate 71 kDa protein 26 Keratin, type I IPI00384444 KRT14 P02533 Decreased cytoskeletal 14 27 Ubiquitin and ribosomal IPI00179330 UBC; UBB; P62979 Decreased protein S27a precursor RPS27A 28 FLJ54957, highly similar to IPI00643920 TKT B4DE31 Increased Transketolase 29 Galectin-1 IPI00219219 LGALS1 P09382 Increased 30 Isoform M1 of Pyruvate IPI00220644 PKM2 E7EUQ8 Decreased kinase isozymes M1/M2 31 Tubulin beta chain IPI00011654 TUBB Q6P602 Decreased 32 Isoform 2 of Nucleophosmin IPI00220740 NPM1 P06748 Decreased 33 Isoform 1 of Nucleoside IPI00026260 NME1; P22392 Increased diphosphate kinase B NME2 34 Thrombospondin-1 IPI00296099 THBS1 P07996 Decreased 35 cDNA FLJ55792, highly IPI00217966 LDHA P00338 Increased similar to L-lactate dehydrogenase A chain 36 Keratin, type II IPI00009867 KRT5 P13647 Increased cytoskeletal 5 37 HSPA5 protein IPI00003362 HSPA5 P11021 Increased 38 Thymosin beta-10 IPI00220827 TMSB10 P63313 Decreased 39 Isoform Long of Laminin IPI00015117 LAMC2 Q2M1N2 Increased subunit gamma-2 40 Keratin, type II IPI00220327 KRT1 P04264 Decreased cytoskeletal 1 41 ADP/ATP translocase 2 IPI00007188 SLC25A5 P05141 Decreased 42 Actin, cytoplasmic 1 IPI00021439 ACTB P60709 Increased 43 Epiplakin 1 IPI00010951 EPPK1 P58107 Decreased 44 Cofilin-1 IPI00012011 CFL1 P23528 Increased 45 Laminin subunit beta-3 IPI00299404 LAMB3 Q13751 Increased 46 Isoform 1 of Heterogeneous IPI00018140 SYNCRIP O60506 Decreased nuclear ribonucleoprotein Q 47 Hemoglobin subunit gamma-1 IPI00220706 HBG1 E7CYP2 Increased 48 Glutathione S-transferase P IPI00219757 GSTP1 P09211 Increased 49 Fructose-bisphosphate IPI00465439 ALDOA P04075 Increased aldolase A 50 60S ribosomal protein L18 IPI00215719 RPL18 Q07020 Decreased 51 EEF2 Elongation factor 2 IPI00186290 EEF2 P13639 Decreased 52 RPL4 11 kDa protein IPI00792159 RPL4 P36578 Increased 53 RPL6 60S ribosomal protein IPI00329389 RPL6 Q02878 Increased L6 54 Keratin 7 IPI00847342 KRT7 P08729 Increased 55 Putative uncharacterized IPI00386854 HNRNPA2B1 P22626 Increased protein HNRNPA2B1 56 Protein S100-A6 IPI00027463 S100A6 P06703 Increased 57 Tudor domain-containing IPI00030153 TDRD6 O60522 Increased protein 6 58 Coiled-coil domain- IPI00477003 KIAA1407 Q8NCU4 Decreased containing protein KIAA1407 59 Histone H2B type 1-L IPI00018534 HIST1H2BL Q99880 Increased 60 Peptidyl-prolyl cis-trans IPI00419585 PPIA A8K220 Increased isomerase A 61 cDNA FLJ53068, highly IPI00643567 CAP1 Q01518 Decreased similar to Adenylyl cyclase-associated protein 1 62 Tu translation elongation IPI00027107 TUFM P49411 Decreased factor, mitochondrial precursor 63 SH3 domain binding glutamic IPI00010402 SH3BGRL3 Q86Z22 Increased acid-rich protein like 3 64 Cornifin-B IPI00304903 SPRR1B P22528 Decreased 65 Isoform Beta-4C of Integrin IPI00027422 ITGB4 P16144 Decreased beta-4 66 60S ribosomal protein L35 IPI00412607 RPL35 P42766 Increased 67 60S ribosomal protein L34 IPI00219160 RPL34 P49207 Decreased 68 Protein S100-A8 IPI00007047 S100A8 P05109 Decreased 69 HSP90B1 Endoplasmin IPI00027230 HSP90B1 P14625 Increased 70 Hemoglobin subunit alpha IPI00410714 HBA2; HBA1 P69905 Increased 71 SFN Isoform 1 of 14-3-3 IPI00013890 SFN P31947 Increased protein sigma 72 HSP90AA1 heat shock 90 kDa IPI00382470 HSP90AA1 E07900 Increased protein 1, alpha isoform 1 73 S100A9 Protein S100-A9 IPI00027462 S100A9 P06702 Decreased 74 cDNA FLJ54408, highly IPI00911039 HSP70.1 B4E3B6 Increased similar to Heat shock 70 kDa protein 1 75 Keratin, type I IPI00450768 KRT17 Q04695 Decreased cytoskeletal 17 76 Heat shock protein beta-1 IPI00025512 HSPB1 P04792 Decreased 77 FASN Fatty acid synthase IPI00026781 FASN P49327 Decreased 78 KRT6A Keratin, type II IPI00300725 KRT6A P02538 Decreased cytoskeletal 6A 79 DSP Isoform DPI of IPI00013933 DSP P15924 Decreased Desmoplakin 80 PRDX1 Peroxiredoxin-1 IPI00000874 PRDX1 Q06830 Increased 81 Protein disulfide-isomerase IPI00010796 P4HB P07237 Increased 82 Histone H1.4 IPI00217467 HIST1H1E P10412 Decreased 83 Isoform 1 of 60S ribosomal IPI00024933 RPL12 P30050 Decreased protein L12 84 Tubulin alpha-4A chain IPI00007750 TUBA4A P68366 Decreased 85 Tubulin beta-3 chain IPI00013683 TUBB3 Q13509 Decreased 86 14-3-3 protein gamma IPI00220642 YWHAG P61981 Increased 87 Vimentin IPI00418471 VIM P08670 Increased 88 Filamin-A IPI00302592 FLNA P21333 Increased 89 Annexin A5 IPI00329801 ANXA5 P08758 Increased 90 40S ribosomal protein S28 IPI00719622 RPS28 P62857 Decreased 91 60S acidic ribosomal IPI00008530 RPLP0 P05388 Increased protein P0 92 Laminin alpha-3 chain IPI00377045 LAMA3 B0YJ32 Increased variant 1 93 Histone H2A type 1-H IPI00081836 HIST1H2AH Q96KK5 Decreased 94 Eukaryotic initiation IPI00025491 EIF4A1 P60842 Increased factor 4A-I 95 Moesin IPI00219365 MSN P26038 Increased 96 Keratin, type I IPI00217963 KRT16 P08779 Decreased cytoskeletal 16 97 Phosphoglycerate mutase IPI00453476 PGAM1 P18669 Increased 98 Protein disulfide-isomerase IPI00025252 PDIA3 P30101 Increased A3 99 Peptidyl-prolyl cis-trans IPI00646304 PPIB P23284 Increased isomerase B 100 Galectin-7 IPI00219221 LGALS7; P47929 Decreased LGALS7B 101 cDNA FLJ45706 fis, clone IPI00444262 NCL E7EX81 Decreased FEBRA2028457, highly similar to Nucleolin 102 Peroxiredoxin-2 IPI00027350 PRDX2 P32119 Increased (A) Group 1 - top 12 skin sensitizer markers; (B) Group 2 - top 6 markers for skin irritation*; (C) Group 3 - additional general markers of sensitizing and irritation effect

[0030] In accordance with this first and other aspects of the invention, determining the presence or change in expression level of the one or more marker proteins may be achieved in many ways all of which are well within the capabilities of the skilled person.

[0031] The determination may involve direct quantification of nucleic acid or protein levels, or it may involve indirect quantification, e.g. using an assay that provides a measure that is correlated with the amount of marker protein present. Accordingly, determining the presence or level of expression of the one or more marker proteins may comprise

[0032] (a) contacting the cell with at least one specific binding member that selectively binds to said marker protein or nucleic acid sequence encoding said marker protein; and

[0033] (b) detecting and/or quantifying a complex formed by said specific binding member and the marker protein or nucleic acid sequence encoding said marker protein.

[0034] The specific binding member may be an antibody or antibody fragment that specifically and selectively binds a marker protein. The determination may include preparing a standard curve using standards of known expression levels of the one or more marker proteins and comparing the reading obtained with the cell contacted with the test compound so as to derive a measure of the change in level of expression of the one or more marker proteins.

[0035] A variety of methods may be suitable for determining the presence or changes in level of expression of the one or more marker proteins: by way of a non-limiting example, these include Western blot, ELISA (Enzyme-Linked Immunosorbent Assay), RIA (Radioimmunoassay), Competitive EIA (Competitive Enzyme Immunoassay), DAS-ELISA (Double Antibody Sandwich-ELISA), Liquid Immunoarray technology), immunocytochemical or immunohistochemical techniques, techniques based on the use of protein microarrays that include specific antibodies, "dipstick" assays, affinity chromatography techniques and liquid binding assays. The specific binding member may be an antibody or antibody fragment that selectively binds the protein marker or part thereof. Any suitable antibody format may be employed.

[0036] A further class of specific binding members contemplated herein in accordance with any aspect of the invention comprise aptamers (including nucleic acid aptamers and peptide aptamers). Advantageously, an aptamer directed to a protein marker may be provided by a technique known as SELEX (Systematic Evolution of Ligands by Exponential Enrichment), described in U.S. Pat. Nos. 5,475,096 and 5,270,163.

[0037] In some embodiments of this and other aspects of the invention, the determination of the presence or the level of expression of one or more of the marker proteins may be performed by mass spectrometry. Techniques suitable for measuring the level of a protein marker selected from Table 1 are readily available to the skilled person and include techniques related to Selected Reaction Monitoring (SRM) and Multiple Reaction Monitoring (MRM) isotope dilution mass spectrometry including SILAC, AQUA (as disclosed in WO 03/016861, the entire content of which is specifically incorporated herein by reference) and TMTcalibrator (as disclosed in WO 2008/110581; the entire content of which is specifically incorporated herein by reference).

[0038] WO 2008/110581 discloses a method using isobaric mass tags to label separate aliquots of all proteins in a reference sample which can, after labelling, be mixed in quantitative ratios to deliver a standard calibration curve. A test sample is then labelled with a further independent member of the same set of isobaric mass tags and mixed with the calibration curve. This mixture is the subjected to tandem mass spectrometry and peptides derived from specific proteins can be identified and quantified based on the appearance of unique mass reported ions released from the isobaric mass tags in the MS/MS spectrum.

[0039] By way of a reference level, a known or predicted protein marker derived peptide may be created by trypsin, ArgC, AspN or Lys-C digestion of said protein marker. In some cases, when employing mass spectrometry based determination of protein markers, the methods of the invention comprises providing a calibration sample comprising at least two different aliquots comprising the protein marker and/or at least one protein marker derived peptide, each aliquot being of known quantity and wherein said biological sample and each of said aliquots are differentially labelled with one or more isobaric mass labels. Preferably, the isobaric mass labels each comprise a different mass spectrometrically distinct mass marker group.

[0040] Accordingly, in a preferred embodiment of the invention, the method comprises determining the presence or expression level of one or more of the marker proteins selected from Table 1 in a cell contacted with a test compound by Selected Reaction Monitoring using one or more determined transitions for known protein marker derived peptides; comparing the peptide levels in the cell under test with peptide levels previously determined to represent contact sensitivity by the cell; and determining the sensitivity potential of the test compound based on changes in expression of said one or more marker proteins. The comparison step may include determining the amount of marker protein derived peptides from the treated cell with known amounts of corresponding synthetic peptides. The synthetic peptides are identical in sequence to the peptides obtained from the cell, but may be distinguished by a label such as a tag of a different mass or a heavy isotope.

[0041] In some embodiments the marker derived peptides are selected from Table 5. In these embodiments the method may comprise determining the presence or expression level of one or more of the marker proteins in a cell contacted with a test compound by Selected Reaction Monitoring using one or more (or a plurality, e.g. two, three, four, five, eight, ten, fifteen, twenty, thirty, forty or all) determined transitions in Table 5; comparing the peptide levels in the cell under test with peptide levels previously determined to represent contact sensitivity by the cell; and determining the sensitivity potential of the test compound based on changes in expression of said one or more marker proteins. The comparison step may include determining the amount of marker protein derived peptides from the treated cell with known amounts of corresponding synthetic peptides. The synthetic peptides are identical in sequence to the peptides obtained from the cell, but may be distinguished by a label such as a tag of a different mass or a heavy isotope.

[0042] In a preferred embodiment the one or more determined transitions include one or more (or a plurality, e.g. two, three, four, five, eight, ten, twelve, or all fifteen) of:

TABLE-US-00002 fragment Peptide TMT m/z m/z ion Collision start stop Analyte Sequence label (Q1) (Q3) type energy time time HSPA8 GTLDPVEK light 653.880455 611.33588 b4 29 9.5 11.6 HSPA8 GTLDPVEK light 653.880455 696.42503 y4 30 9.5 11.6 HSPA8 GTLDPVEK light 653.880455 811.451973 y5 31 9.5 11.6 HSPA8 TVTNAVVTVPA light 736.053596 640.362429 b4 47 11.2 12.9 YFNDSQR HSPA8 TVTNAVVTVPA light 736.053596 711.399543 b5 36 11.2 12.9 YFNDSQR HSPA8 TVTNAVVTVPA light 736.053596 810.467957 b6 32 11.2 12.9 YFNDSQR S100A8 ALNSIIDVYHK light 574.335375 610.351865 b4 31 11.4 12.9 S100A8 ALNSIIDVYHK light 574.335375 723.435929 b5 27 11.4 12.9 S100A9 LGHPDTLNQGE light 635.34471 704.39373 y4 25 10 11.6 FK S100A9 NIETIINTFHQ light 752.416646 682.372994 b4 42 12.4 14.2 YSVK S100A9 NIETIINTFHQ light 752.416646 720.42503 y4 35 12.4 14.2 YSVK S100A9 NIETIINTFHQ light 752.416646 795.457058 b5 38 12.4 14.2 YSVK TYB10 ETIEQEK light 662.867545 628.362429 y3 34 8.4 10.5 TYB10 ETIEQEK light 662.867545 697.37266 b4 37 8.4 10.5 TYB10 ETIEQEK light 662.867545 757.405023 y4 34 8.4 10.5

[0043] One or more of these synthetic protein marker derived peptides with or without label form a further aspect of the present invention. These synthetic peptides may be provided in the form of a kit for the purpose of determining the sensitising potential of a test compound. In this aspect, the synthetic peptides may comprise or consist of a sequence of a peptide selected from Table 5.

[0044] Other suitable methods for determining levels of protein expression include surface-enhanced laser desorption ionization-time of flight (SELDI-TOF) mass spectrometry; matrix assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry; electrospray ionization (ESI) mass spectrometry; as well as the preferred SRM.

[0045] In some embodiments, the determination of the presence or amount of the one or more protein markers comprises measuring the presence or amount of mRNA derived from the cell under test. The presence or level of mRNA encoding the protein marker in the cells contacted with the test compound provides a determination of whether the test compound has a sensitizing potential. Techniques suitable for measuring the level of protein marker encoding mRNA are readily available to the skilled person and include "real-time" reverse transcriptase PCR or Northern blots. The method of measuring the level of a protein marker encoding mRNA may comprise using at least one primer or probe that is directed to the sequence of the protein marker encoding gene or complement thereof. The at least one primer or probe may comprise a nucleotide sequence of at least 10, 15, 20, 25, 30 or 50 contiguous nucleotides that has at least 70%, 80%, 90%, 95%, 98%, 99% or 100% identity to a nucleotide sequence encoding the protein marker provided in Table 1 and FIG. 10.

[0046] Preferably, the at least one probe or primer hybridises under stringent conditions to a protein marker encoding nucleic acid sequence.

[0047] The method of the invention may comprises contacting the cell with a binding member as described above, but also includes contacting the binding member with culture medium around the cells which may contain products secreted by the cells. Further, it may be preferably to lyse the cell prior to contact with the binding member to increase contact directly or indirectly with the one or more marker proteins.

[0048] The binding members may be immobilised on a solid support. This may be in the form of an antibody array or a nucleic acid microarray. Arrays such as these are well known in the art. The solid support may be contacted with the cell lysate or culture medium surrounding the cell, thereby allowing the binding members to bind to the cell products or secreted products representing the presence or amount of the one or more marker proteins.

[0049] In some embodiments, the binding member is an antibody or fragment thereof which is capable of binding to a marker protein or part thereof. In other embodiments, the binding member may be a nucleic acid molecule capable of binding (i.e. complementary to) the sequence of the nucleic acid to be detected.

[0050] The method may further comprise contacting the solid support with a developing agent that is capable of binding to the occupied binding sites, unoccupied binding sites or the one or more marker proteins, antibody or nucleic acid.

[0051] The developing agent may comprise a label and the method may comprise detecting the label to obtain a value representative of the presence or amount of the one or more marker proteins, antibody or nucleic acid in the cell, cell culture medium or cell lysate.

[0052] The label may be, for example, a radioactive label, a fluorophor, a phosphor, a laser dye, a chromogenic dye, a macromolecular colloidal particle, a latex bead which is coloured, magnetic or paramagnetic, an enzyme which catalyses a reaction producing a detectable result or the label is a tag.

[0053] The method may comprise determining the presence or level of expression of a plurality of marker proteins or nucleic acids encoding said marker proteins in a single sample. For example, a plurality of binding members selected from Table 1, Table 1 (A) Group 1; Table 1 (B) Group 2; or Table 1 (C) Group 3 or a combination thereof, may be immobilised at predefined locations on the solid support. The number of binding members selected from Table 1 on the solid support may make up 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% of the total number of binding members on the support.

[0054] Alternatively, a plurality of mass features are selected for mass spectrometry techniques described above.

[0055] The binding member may be an antibody specific for a marker protein or a part thereof, or it may be a nucleic acid molecule which binds to a nucleic acid molecule representing the presence, increase or decrease of expression of a marker protein, e.g. an mRNA sequence.

[0056] The antibodies raised against specific marker proteins may be anti- to any biologically relevant state of the marker protein. Thus, for example, they can be raised against the unglycosylated form of a protein which exists in the body in a glycosylated form, against a precursor form of the protein, or a more mature form of the precursor protein, e.g. minus its signal sequence, or against a peptide carrying a relevant epitope of the marker protein.

[0057] In a second aspect of the invention, there is provided a kit for use in determining the sensitizing potential of a test compound in vitro. The kit allows the user to determine the presence or level of expression of an analyte selected from one or more marker proteins or fragments thereof provided in Table 1, one or more antibodies against said marker proteins and a nucleic acid molecule encoding said marker protein or a fragment thereof, in a cell under test; the kit comprising

[0058] (a) a solid support having a binding member capable of binding to the analyte immobilised thereon;

[0059] (b) a developing agent comprising a label; and, optionally

[0060] (c) one or more components selected from the group consisting of washing solutions, diluents and buffers.

[0061] The binding member may be as described above. In particular, for detection of a marker protein or fragment thereof, the binding member may be an antibody which is capable of binding to one or more of the marker proteins selected from Table 1, Table 1 (A) Group 1; Table 1 (B) Group 2; or Table 1 (C) Group 3 or a combination thereof.

[0062] In one embodiment, the kit may provide the analyte in an assay-compatible format. As mentioned above, various assays are known in the art for determining the presence or amount of a protein, antibody or nucleic acid molecule in a sample. Various suitable assays are described below in more detail and each form embodiments of the invention.

[0063] The kit may be used in an in vitro method of determining sensitizing potential of a test compound. This method may be performed as part of a general screening of multiple samples, or may be performed on a single sample obtained from the individual.

[0064] The kit may additionally provide a standard or reference which provides a quantitative measure by which determination of an expression level of one or more marker proteins can be compared. The standard may indicate the levels of marker protein expression which indicate contact sensitivity to said compound.

[0065] The kit may also comprise printed instructions for performing the method.

[0066] In one embodiment, the kit for the determination of sensitizing potential of a test compound contains a set of one or more antibody preparations capable of binding to one or more of the marker proteins provided in Table 1, a means of incubating said antibodies with a cell exposed to said test compound or extract obtained from said cell, and a means of quantitatively detecting binding of said proteins to said antibodies. The kit may also contain a set of additional reagents and buffers and a printed instruction manual detailing how to perform the method and optionally how to interpret the quantitative results as being indicative of contact sensitivity to said compound.

[0067] In a further embodiment, the kit may be for performance of a mass spectrometry assay and may comprise a set of reference peptides (e.g. SRM peptides) in an assay compatible format wherein each peptide in the set is uniquely representative of each of the one or more marker proteins described provided in Table 1, Table 1 (A) Group 1; Table 1 (B) Group 2; or Table 1 (c) Group 3 or a combination thereof. Preferably two and more preferably three such unique peptides are used for each protein for which the kit is designed, and wherein each set of unique peptides are provided in known amounts which reflect the levels of such proteins in a standard preparation of said cell exposed to a known sensitizing compound. Optionally the kit may also provide protocols and reagents for the isolation and extraction of proteins from said cell, a purified preparation of a proteolytic enzyme such as trypsin and a detailed protocol of the method including details of the precursor mass and specific transitions to be monitored. Optionally, the kits of the present invention may also comprise appropriate cells, vessels, growth media and buffers.

[0068] In a third aspect of the invention, there is provided a method for the diagnosis or prognostic monitoring of contact sensitizing by an allergen or irritant on an individual exposed to said allergen or irritant the method comprising determining the presence or level of expression of one or more protein markers selected from Table 1, Table 1 (A) Group 1; Table 1 (B) Group 2; or Table 1 (c) Group 3, or a nucleic acid encoding any one or said protein markers or part thereof, in biological sample obtained from said individual.

[0069] The biological sample is preferably a sample comprising cells from the individual, e.g. skin cells. The cells may be lysed and the determination step carried out on the cell lysate. The determination step may be performed as described in the first aspect of the invention.

[0070] The method may include determining the presence or level of expression of one or more protein markers in a plurality of biological samples taken over a period of time to create a time line, where contact with the allergen or irritant is time zero.

[0071] There is also provided a kit for carrying out the method according to the third aspect of the present invention.

[0072] The kit may comprise

[0073] (a) a solid support having one or more binding member immobilised thereon, wherein each binding member selectively binds to a protein marker selected from the group provided in Table 1, Table 1 (A) Group 1; Table 1, (B) Group 2; or Table 1 (c) Group 3; or a nucleic acid, encoding the protein marker or fragment thereof;

[0074] (b) a developing agent comprising a label; and

[0075] (c) one or more components selected from washing solutions, diluents and buffers.

[0076] The kit may also comprise printed instructions for performing the method.

[0077] The kit may additionally provide a standard or reference which provides a quantitative measure by which determination of an expression level of one or more marker proteins can be compared. The standard may indicate the levels of marker protein expression which indicate contact sensitivity to said compound.

[0078] Likewise, expression levels of one or more proteins selected from Table 1, Table 1 (A) Group 1; Table 1, (B) Group 2; or Table 1 (c) Group 3, may be measured in a tissue sample taken from an individual having been exposed to an allergen or irritant and the levels compared to those from cells having had no exposure to the allergen or irritant; where a change in protein expression level consistent with the changes described in Table 1 is diagnostic of an induced allergy.

[0079] The determination of specific proteins whose expression levels are altered following exposure to a chemical sensitizer, e.g. an allergen or irritant, provides for the first time new targets for the diagnosis and treatment of chemically induced allergic conditions such as contact dermatitis.

[0080] Accordingly, in a fourth aspect of the present invention, there is provided the use of one or more protein markers selected from Table 1, Table 1 (A) Group 1; Table 1 (B) Group 2; or Table 1 (c) Group 3 for the diagnosis or prognostic monitoring of an individual to chemical sensitizers such as an allergen or irritant.

[0081] For example, a plurality of protein markers from Table 1, Table 1 (A) Group 1; Table 1 (B) Group 2; or Table 1 (c) Group 3, may be used in a method of monitoring the effectiveness of treatment for skin allergy or irritation on a patient suffering from said allergy or irritation. The method may comprise determining changes in the presence or levels of expression of said protein marker (e.g. by a method of the first aspect of the invention), in a tissue sample obtained from said individual prior to treatment and one or more further samples taken post treatment or during the course of treatment; wherein a returning to normal expression levels for the plurality of protein markers is indicative if successful treatment.

[0082] In an embodiment of this aspect of the invention, the treatment may be specifically designed to target one or more of the plurality of protein markers selected from Table 1, Table 1 (A) Group 1; Table 1 (B) Group 2; or Table 1 (c) Group 3. Accordingly, the invention extends to the provision of the use of one or more protein markers provided in Table 1, Table 1 (A) Group 1; Table 1 (B) Group 2; or Table 1 (c) Group 3, or parts thereof as targets for treatment for a skin allergy.

[0083] In all aspects of the invention, the methods are in most cases in vitro methods carried out on a sample from a primary cell culture, an established cell line or a biopsy sample taken from a patient suffering from a contact allergy e.g. ACD, irritation. The sample used in the methods described herein may be a whole cell lysate, subcellular fraction e.g. cytoplasm, nucleus, mitochondria, cell membranes, cell culture medium supernatant, tissue or body fluid sample, for example a skin tissue sample, bronchoalveolar lavage (BAL) fluid, blood or a blood product (such as serum or plasma) sample or a urine sample.

[0084] In all aspects and in all embodiments of the invention, the one or markers selected from Table 1, Table 1 (A) Group 1; Table 1 (B) Group 2; or Table 1 (c) Group 3 may be with the proviso that the marker is not one or more, or a combination of isoform 1 of Heat Shock cognate 71 kDa protein; Protein S100-A8; Protein S100-A9; ADP/ATP translocase 2; Peptidyl-prolyl cis-trans isomerase A; Histone H2B type 1-L; Tubulin alpha-4A chain; protein disulfide-isomerase; Tu translation elongation factor mitochondrial precursor; Vimentin; SH3 domain binding glutamic acid-rich protein like 3; protein disulfide-isomerase A3; Annexin A5; Isoform 2 of Filamin-A; Galectin-1; Thioredoxin; Peroxiredoxin; Heat shock protein 90 kDa alpha (cytosolic), class A member 1 isoform 1; Elongation factor 2; Fructose-bisphosphate aldolase A; Glyceraldehyde-3 phosphate dehydrogenase; Elongation factor 1-alpha; cDNA FLJ45706 fis, clone FEBRA2028457, highly similar to Nucleolin; and Isoform 2 of Nucleophosmin.

[0085] Embodiments of the present invention will now be described by way of example and not limitation with reference to the following accompanying figures. All documents mentioned herein are incorporated herein by reference.

BRIEF DESCRIPTION OF THE FIGURES

[0086] FIG. 1: PLS loading plot of ANOVA filtered biomarkers found in human primary keratinocytes, wherein R2X[1]=0,210301 R2X[2]=0,224212.

[0087] FIG. 2: PLS score plot showing good separation between sensitizer and irritant exposed samples using biomarkers listed in Table 1.

[0088] FIG. 3: ELISA Quantification of Heat shock 70 kDa protein 1 (HSPA1A; HSPA1B) in keratinocytes

[0089] FIG. 4: Western Blot quantification of aldo-keto reductase C1 (AKRC1) in keratinocyte cell extracts

[0090] FIG. 5: Western Blot quantification of metallothionein 1G (MT1G) in keratinocyte cell extracts

[0091] FIG. 6: Log2-transformed and referenced fold changes of 102 protein biomarkers Diamond: allergen; circle: irritant; rectangle: control.

[0092] FIG. 7: Differences in the relative abundance of 102 protein biomarkers between test chemicals. Control: diamond; Nickel: cross; TMTD: plus sign; CA: asterisk; SDS: downward-pointing triangle; DNBS: square; DNCB: circle; SA: upward-pointing triangle.

[0093] FIG. 8: Table 4--Protein Sequence Table.

[0094] FIG. 9: Table 5--List of peptides, transition masses and mass spectrometer settings for TSQ Vantage (Thermo Scientific) used in the SRM assay

DEFINITIONS

[0095] The term "antibody" includes polyclonal antiserum, monoclonal antibodies, fragments of antibodies such as single chain and Fab fragments, and genetically engineered antibodies. The antibodies may be chimeric or of a single species.

[0096] The term "marker protein" or "biomarker" includes all biologically relevant forms of the protein identified, including post-translational modification. For example, the marker protein can be present in a glycosylated, phosphorylated, multimeric or precursor form.

[0097] The term "control" refers to a cultured cell line, primary culture of cells taken from a human or animal subject, or biopsy material taken from a human or animal subject that has been incubated with an equivalent buffer to the test cells but lacking any test compound.

[0098] The terminology "increased/decreased concentration . . . compared with a control sample" does not imply that a step of comparing is actually undertaken, since in many cases it will be obvious to the skilled practitioner that the concentration is abnormally high or low. Alternatively, the previously determined normal levels after exposure to non-sensitizing chemicals may be used as a reference value.

[0099] The term "antibody array" or "antibody microarray" means an array of unique addressable elements on a continuous solid surface whereby at each unique addressable element an antibody with defined specificity for an antigen is immobilised in a manner allowing its subsequent capture of the target antigen and subsequent detection of the extent of such binding. Each unique addressable element is spaced from all other unique addressable elements on the solid surface so that the binding and detection of specific antigens does not interfere with any adjacent such unique addressable element.

[0100] The term "bead suspension array" means an aqueous suspension of one or more identifiably distinct particles whereby each particle contains coding features relating to its size and colour or fluorescent signature and to which all of the beads of a particular combination of such coding features is coated with an antibody with a defined specificity for an antigen in a manner allowing its subsequent capture of the target antigen and subsequent detection of the extent of such binding. Examples of such arrays can be found at www.luminexcorp.com where application of the xMAP® bead suspension array on the Luminex® 100® System is described.

[0101] The terms "selected reaction monitoring", "SRM" and "MRM" means a mass spectrometry assay whereby precursor ions of known mass-to-charge ratio representing known biomarkers are preferentially targeted for analysis by tandem mass spectrometry in an ion trap or triple quadrupole mass spectrometer. During the analysis the parent ion is fragmented and the number of daughter ions of a second predefined mass-to-charge ratio is counted. Typically, an equivalent precursor ion bearing a predefined number of stable isotope substitutions but otherwise chemically identical to the target ion is included in the method to act as a quantitative internal standard. Examples of such methods can be found at http://en.wikipedia.org/wiki/Selected_reaction_monitoring.

[0102] The term "sensitizer" means a chemical that induces an allergic response in exposed people or animals after repeated exposure to the chemical.

[0103] "Skin sensitization" means an immunological process which is induced when a susceptible individual is exposed topically to the inducing chemical allergen.

[0104] "Sensitizing potential" means the potential of a chemical compound or element to cause skin damage through topical exposure which may be by topical exposure. For the present purposes, the sensitizing potential of a compound includes its potential to cause damage via an allergic response (a sensitizer) and/or via inflammation (an irritant).

[0105] "Irritant" means a chemical that causes an inflammatory effect on living tissue by chemical action at the site of contact. It is important to include irritating chemicals when developing biomarkers for skin sensitization, because sensitizers (i.e. DNCB) can also exert irritation.

[0106] Chemicals which do not induce sensitization are referred to as "non-sensitizer", but may also include irritants.

DETAILED DESCRIPTION

[0107] The need for testing of chemical safety is a long established part of the regulatory process for pharmaceuticals and for the approval for sale of cosmetics and a wide range of other products that come into contact with human skin and mucosa. A number of testing regimes have been established and in some cases only a small number of these tests are proscribed as fit for purpose by national regulators. In the main these tests have been based on whole living organism studies, typically in rodent species.

[0108] There is now a strong ethical and economic driver to reduce the number of animals used in pharmaceutical and chemical safety testing and a concomitant need to find suitable in vitro tests to replace the proscribed testing methods. In this context we set out to demonstrate a set of proteins whose levels of expressions within a cultured cell line or tissue biopsy alter in a predictable manner in response to allergenic or irritant compounds.

[0109] To discover such a set of proteins we applied a proprietary proteomics discovery workflow to a human primary keratinocytes cultured in vitro. In brief, keratinocytes were cultured in the presence of known allergenic sensitizers, non-allergenic irritants or remained untreated. Keratinocytes were exposed to low and high dose of chemicals to look for dose effects. After exposure the keratinocytes were harvested and lysed and proteins extracted. Following extraction, the total cell lysate was subjected to proteolysis using trypsin and the resultant peptides labelled with one of a sixplex set of isobaric mass tags (Tandem Mass Tags®, Proteome Sciences plc).

[0110] Tandem Mass Tags are designed to allow the discriminant labelling of up to six different samples prior to mixing and analysis of all six samples in a single mass spectrometry experiment. Each tag in the set has the same overall mass (isobaric) but on fragmentation in the mass spectrometer releases a unique reporter ion whose intensity relative to the other reporter ions is directly proportional to the relative abundance of the protein in the sample. In our discovery experiments we were able to obtain relative quantitative information for 4245 peptides representing 1980 unique proteins consistently measured in at least 50% of all mass spectrometric measurements in a time- and cost-effective manner.

[0111] By allowing early mixing of samples the use of Tandem Mass Tags increases the robustness of the data allowing selection of the best candidates for subsequent routine measurement in a targeted screening test with higher throughput than discovery methods. However, to identify those proteins whose expression is predictably altered by chemical exposure it is necessary to undertake a panel of statistical analyses such as supervised and un-supervised cluster analysis. Through selective application of a range of such statistical tools we identified 102 protein markers that were significantly regulated in response to exposure to a set of training chemicals. Within these 102 proteins are markers of contact as well as non-sensitizing irritants.

[0112] Following the identification of candidate biomarkers using a set of training chemicals we developed a classification model that could predict whether a compound was a sensitizer/allergen or a non-sensitizing irritant based on the detected amount of one or more of the 102 biomarkers listed in Table 1. This classification model can be used to interpret the protein expression data from keratinocytes exposed to unknown chemicals or combinations of chemicals and to assign said chemicals into the allergen or irritant group. This test system is therefore suitable to replace living, whole-organism test for chemical safety.

[0113] It is recognised that the discovery methods used in this study are less well suited to the routine analysis of hundreds, thousands or tens of thousands of chemicals with unknown safety profile, such as will be needed to meet the ethical need to replace animal testing and the pending EU legislation. To overcome this potential bottleneck it will be necessary to provide more targeted means of analysis of one or more of the 102 protein biomarkers listed in Table 1. There are a number of suitable methods for the targeted measurement of up to 102 different proteins in a single analysis. One such technology is immunoassay where antibodies with specificity for the biomarker protein are used to capture, detect or capture and detect the protein. Immunoassay formats include but are not limited to enzyme-linked immunosorbent assay (ELISA), antibody sandwich ELISA, competitive ELISA, immunoPCR and Western blot. Where a small number of proteins are to be measured it is possible to use individual tests such as ELISA or western blot for each protein. Alternatively, multiplex testing methods such as antibody arrays and/or bead suspension arrays where a plurality of biomarkers are detected and quantified simultaneously can be used.

[0114] In some cases it may be undesirable or impossible to use antibodies to selectively quantitate levels of protein expression. Examples include where the biomarker is post-translationally modified as a result of chemical exposure and such modification is immunologically inert, or where proteolytic activity causes degradation of a protein thereby destroying epitopes recognised by available antibodies. In such situations non-antibody binding agents such as aptamers may be used. More preferably, quantitative mass spectrometry methods can be developed based on the principle of selected reaction monitoring (SRM).

[0115] In an SRM method peptides representing the target marker protein are selected based on empirical data obtained during marker discovery or are designed using in silico tools. Typically a combination of the two approaches is used for best results. For absolute quantitation by SRM it is necessary to provide an external equivalent `heavy` peptide that is isotopically distinct to the native form to be measured in the analytical sample. There are a number of different approaches for the provision of such isotopically distinct reference peptides though they all share the common feature of adding one or more heavy stable isotopes into the peptide during production. The simplest approach which is often termed `AQUA` is to use an amino acid containing one or more stable isotopes of hydrogen, carbon, nitrogen or oxygen. Typically a combination of isotopes is used to introduce a total mass difference of between 6 and 10 Daltons per peptide. There are a number of commercial sources of such heavy AQUA peptides (e.g. Thermo Scientific (www.thermoscientific.com)). An alternate to AQUA is to add heavy isotopes through a covalent label attached to a standard synthetic peptide. Such methods have the advantage of speed and cost of production of the reference peptides. However, the method then requires use of an isotopically distinct but chemically identical tag to label each analytical sample. There are a number of approaches for tag-based SRM methods including mTRAQ® (ABSciex) and TMT® (Thermo Scientific). Where multiple reference peptides are required it is possible to manufacture a synthetic gene encoding all desired peptides in a concatamer polypeptide. This is then transfected into a suitable expression host or in vitro transcription system and the expressed polypeptide purified prior to cleavage to release the individual reference peptides. Typically this would be performed using a heavy amino acid to provide the isotope substitution such that all peptides are `heavy` relative to the natural form in the analytical sample. An example of such a method is the QCONCAT system (Pratt et al. Nature Protocols 1, -1029-1043 (2006)).

[0116] It will be understood by the skilled practitioner that the method of detection is not particularly limiting to the present invention and all methods of relative or absolute quantitation of the target proteins are incorporated herein.

[0117] Human keratinocytes were used as a skin keratinocyte cell culture model for developing a protein biomarker based in vitro assay system for determining the sensitizing potential of chemical sensitizers. It is consequently an additional aspect of the invention that these protein markers can also be used for the diagnosis of skin allergy in a mammal or human suspected of suffering from such an allergy. In this context a suitable tissue sample such as biopsy samples of skin or bronchoalveolar lavage are collected, proteins extracted and measured according to one of the methods of the present invention. The levels detected in the said sample are then compared with the levels known to be associated with a response to sensitizing agents in keratinocytes. It is a further aspect of the invention that the presently disclosed proteins provide alternate means for the treatment of chemically induced allergy such as contact dermatitis and asthma.

[0118] Four biomarker candidates HSPA8, S100A8, S100A9 and TYMB10 were chosen to develop a specific skin sensitization test for Nickel. In particular, the level of the three proteins HSPA8 and S100A9/A8 (synonyma: Calgranulin A/B; Calprotectin) is strongly and significantly altered by Nickel, whereas TYMB10 is used as a biomarker indicating if a chemical has the property of inducing skin irritation. Although Nickel is a common cause of allergic contact dermatitis in mice, it has been impossible to develop assays for this Nickel in mice (Kimber et al. 2011). The intended use of this assay is to determine the skin sensitization potential of Nickel salts in conjunction with testing the irritating potential of these chemicals in in vitro assays.

[0119] The invention is further illustrated by the following experiments.

Example 1

Proteomic Analysis of a Skin Keratinocyte Model

Training Chemicals Used for the Discovery of Candidate Biomarkers

[0120] A set of training chemicals was selected for biomarker discovery in human keratinocytes. The selected chemicals comprised 5 skin sensitisers of different strength, and 2 non-sensitisers/irritants (Table 2).

Contact Sensitizers/Allergens:

[0121] DNCB: 1-chloro-2,4-dinitrobenzene (DNCB), is a organic compound used in colour photography processing. DNCB is considered an extreme allergen.

[0122] DNBS: 2,4-Dinitrobenzenesulfonic acid is yellow-tan powder used to prepare ether-soluble DNP derivatives of amino alcohols. DNBS is a strong contact sensitizer.

[0123] Cinnamic aldehyde: 3-phenyl-2-Propenal; Cinnamal, Cinnamaldehyde is an oily yellow liquid with strong odor of cinnamon. This compound is the main component of cinnamon oil. The predominant application for cinnamaldehyde is in the flavour and fragrance industries. It is used as a flavouring for chewing gum, ice cream, candy, and beverages. Cinnamic aldehyde is considered a moderate sensitizer.

[0124] TMTD: Tetramethyl thiuram disulfide, thiram, thiuram, or Sovchem® is white powder or granule. TMTD is a fungicide used a seed protectant and to protect fruit, vegetable, crops from a variety of fungal diseases and from damage by rodents and rabbits. TMTD is moderate sensitizer.

[0125] Nickel: Nickel is a silvery-white metal that is mixed to produce alloys. It is used to manufacture stainless steel, coins, body piercings or jewellery. Although Nickel is a weak sensitizer it is a common course of contact allergy.

Irritating/Non-Sensitizing Chemicals:

[0126] SDS: Sodium sodium dodecyl sulfate (SDS), lauryl sulfate (SLS) or sodium laurilsulfate is an anionic surfactant used in many cleaning and hygiene products. SDs can cause skin and eye irritation.

[0127] Salicylic acid: is also known as 2-hydroxybenzenecarboxcylic acid. Salicylic acid is known for its ability to ease aches and pains and reduce fevers. Salicylic acid is a key ingredient in many skin-care products for the treatment of acne, psoriasis, calluses, corns, keratosis pilaris, and warts. Because of its effect on skin cells, salicylic acid is used in several shampoos used to treat dandruff. Exposure to salicylic acid can cause hypersensitivity.

Cell Culture

[0128] Primary human keratinocytes were obtained from Provitro (Berlin, Germany). Cells were seeded at 3×10E5 cells per 10 cm dish. Cells were grown in serum free supplemented keratinocyte growth medium (Provitro) to 80-90% density prior to treatment. Cells were grown at 37° C. in 5% CO2. Second and third passages post-cryopreserved seedings were used for experiments

Chemical Exposure of Cells

TABLE-US-00003

[0129] TABLE 2 List of reference chemicals used to discover biomarkers LLNA Chemical/ Final test concentration EC3 Chemical Solvent Low High (%) 2,4- DNBS in 4 μM 8 μM 1.98 Dinitrobenzenesulfonic DMSO (strong) acid (DNBS) Dinitrochlorobenzene DNCB in 4 μM 8 μM 0.05 (DNCB) DMSO (extreme) Cinnamic aldehyde CA in 38 μM 136 μM 2.8 (CA) DMSO (moderate) Tetramethylthiuram TMTD in 8.3 μM 13.3 μM 5.2 disulfide (TMTD) DMSO (moderate) Nickel Sulfate Ni in 250 μM 1.500 μM False saline negative Sodium dodecyl SDS in 49 μM 60 μM 14 (False sulphate (SDS) saline positive) Salicylic acid (SA) SA in 250 μM 5000 μM Non- DMSO sensitizer

[0130] Test chemicals were added and the plates were incubated for 24 hours at 37° C. in a 5% CO2 humidified incubator. When a chemical was dissolved in DMSO, a final concentration of 0.1% DMSO was used in the relevant negative control. After 24 h incubation, cells were harvested and washed twice in PBS.

Cell Lysis and Sample Preparation

[0131] Cells were lysed in four volumes of 100 mM TEAB (triethylammonium bicarbonate), pH 8.5+0.1, 1 mM TCEP (tris[2-carboxyethyl]phosphine*HCl), 0.1% SDS. After suspending the cell pellet in lysis buffer the suspension was heated at 95° C. for ten minutes in a thermomixer ([Eppendorf, Thermomixer comfort). Cell lysates were sonicated twice on ice for two minutes followed by a second cycle heating and sonication. Samples were then centrifuged at 14.000 g for ten minutes and supernatants were used for further analyses or stored at -80° C.

Determination of Protein Concentrations

[0132] The protein concentration was determined using the Bradford reagent. The results were calculated using a standard curve created from measurements of dilutions of a standard consisting of BSA/IgG (50%/50%).

Trypsin Digestion and Isobaric Mass Tag Labelling

[0133] Tandem Mass Tags (TMTs) (Thermo Scientific) comprise a set of amine-reactive isobaric labels, which are synthesized with heavy and light isotopes to present the same total mass but to provide reporter-ions at different masses after activation with collision-induced dissociation (CID) and subsequent tandem mass spectrometry (MS/MS).

[0134] Equivalents of up to 100 μg protein solution per sample were used for proteomics profiling experiments. A reference pool was created from an aliquot of all samples and included in each TMTsixplex labelling reaction. The final volume of the sample was adjusted with TMT labelling buffer (100 mM TEAB pH 8.4-8.6, 0.1% SDS) to 100 μl per sample. The samples were reduced for 30 min at room temperature by the addition of 5.3 μL each of 20 mM TCEP in water and subsequently alkylated for 1 h at room temperature by the addition of 5.5 μL each of 150 mM iodoacetamide in acetonitrile.

[0135] For protein digestion, 10 μL of a 0.4 μg/μL trypsin solution (sequencing grade modified trypsin, Promega) in 100 mM TEAB buffer pH 8.4-8.6 was added to each vial and incubated at 37° C. for 18 h. The digested protein samples were labelled with the TMTsixplex reagents TMT6-126, TMT6-127, TMT6-128, TMT6-129, TMT6-130 and TMT6-131). TMTsixplex reagents were dissolved in acetonitrile to yield a concentration of 60 mM and 40.3 μL of the corresponding reagent solution were added to the sample vials and samples incubated for 1 h at room temperature. To reverse occasional labelling of Tyr, Ser and Thr residues, 8 μL of an aqueous hydroxylamine solution (5% w/v) was added and incubated for 15 min at room temperature. The TMTsixplex-labelled samples were combined and purified.

Sample Purification

[0136] The samples were diluted with 3 mL water/acetonitrile 95:5+0.1% TFA each and desalted using HLB Oasis cartridges (1 cc, 30 mg, Waters). The eluate fraction each was further purified by strong cation exchange using self-made cartridges (CHROMABOND empty columns 15 ml, Macherey-Nagel, filled with 650 μL SP Sepharose Fast Flow, Sigma). After loading the peptides and washing with 4 mL water/acetonitrile 75:25+0.1% TFA, the peptides were eluted with 2 mL H₂O:ACN 75:25+400 mM ammonium acetate. The samples were dried in a vacuum concentrator and dissolved in 50 μL water/acetonitrile 95:5+0.1% TFA each and stored at -20° C. until analysis.

Liquid Chromatography and Tandem Mass Spectrometry (LC-MS/MS)

[0137] The TMTsixplex labelled samples were measured by High-Performance Liquid Chromatography-Tandem Mass Spectrometry (HPLC-MS/MS). For example, 5 μL (5 μg) of each sample were injected and measured using an electrospray ionization linear ion trap quadrupole Orbitrap mass spectrometer (Thermo Scientific) operated in CID (collision-induced dissociation) and HCD (higher collision decomposition) mode. The peptide mixture was separated on an Eksigent NanoLC using a Reprosil C18 trapping column (10×0.1 mm, 5 um) and a Reprosil C18 analytical column (400×0.075 mm, 3 um) at a flow rate of 350 nL/min (60 min gradient: 5-30% acetonitril). Instrument parameters were: Resolution (MS=30,000; MS/MS=7,500), collision energy (CID=35 and HCD=75) isolation width (CID=2 u, HCD=1.5 u).

[0138] Peaks lists were generated from Orbitrap raw data files as mascot generic files (*.MGf data files) using Proteome Discoverer (version1.1; ThermoFisher, San Jose, USA). The resulting *.mgf files were searched against the IPI human database (version 3.68 from February 2011) by MASCOT (version 2.2; MatrixScience, London, UK (Probability-based protein identification by searching sequence databases using mass spectrometry data. Perkins D N, Pappin D J, Creasy D M, Cottrell J S. Electrophoresis. 1999 December; 20(18):3551-67.)). Peptide and protein identification was performed using the following parameters:

Carbamidomethyl at Cysteines and TMT modifications at N-terminal site and at Lysines were set as fixed modifications. Trypsin was used for the enzyme restriction, with three allowed miscleavages and an allowed mass tolerance +/-10 ppm for the precursor masses and 0.05 for the fragment ion mass. The corresponding MASCOT result files (*.dat data file) were downloaded and reporter ion intensities and protein identifications were extracted with an in-house tool. Reporter ion intensities and protein identities were exported into a relational MySQL database (version 5.157; Oracle, Redwood Shores, USA) and log 2 ratios of reporter ions were calculated.

Data Pre-Processing of Extracted Reporter Ion Intensities and Relative Quantitation

[0139] The six reporter ion intensities of the isobaric mass tags were corrected for isotopic distribution and systematic bias by means of sum scaling based on the assumption of a constant integral of any reporter ion series within one LC/MS/MS run. In addition, those MS/MS scans were filtered out where the reporter ion intensity of all six tags was smaller than 80 AU (arbitrary units) and where the reporter ion intensity of less than two tags was smaller than 10 AU. The relative intensities of reporter ions represent the relative amount of a peptide in the sample. To compare the relative amount of a peptide to all samples, a ratio is calculated between each sample versus the pooled reference sample. In some experiments each sample a ratio was calculated between each sample and a respective control sample generated from the same donor. The ratio was log 2 transformed to yield referenced measurement values for each peptide. To obtain information on relative changes on the protein level, the log 2 reference reporter ion intensities for each identified peptide belonging to one protein identity were averaged as the geometric mean.

Example 2

Statistical Analysis and Generation of a Classification Model

[0140] Reference chemicals belonging to the groups of sensitizer and irritant as well as appropriate (vehicle) controls were used to select candidate protein biomarkers. These chemicals were applied in two different concentrations to look for concentration dependent effects.

[0141] For multiple hypothesis testing an analysis of variance (ANOVA, p<=0.05) was computed to investigate biomarkers related to any of the possible contrasts between the three classes. To account for variance introduced from analysing different donors and biological replicates linear mixed-effects models (LME) were used to identify biomarker. The statistical scripting language R or the data analysis software MeV (TIGR) version 4.3 was used for all statistical analyses.

[0142] Thereafter, a list of 102 protein biomarker was obtained (No. 1 to 102). The list is detailed in Table 1 and in the protein sequence Table 4 (FIG. 8).

Identification of Candidate Protein Biomarkers for the Assay

[0143] To discover candidate protein biomarkers that are allow discriminating between sensitizer and non-sensitizer two four discovery studies comprising training chemicals listed in Table 2 were performed as described below.

[0144] In the first study keratinocytes obtained from donor were incubated with two irritants 45 μM SDS, 60 μM SDS, 250 μM SA and 500 μM SA) 5 sensitizers (38 μM CA, 136 μM CA, 4 μM DNBS, 8 μM DNBS, 4 μM DNCB, 8 μM DNCB, 8.3 μM TMTD, 13.3 μM TMTD, 250 μM Nickel and 1500 μM Nickel) and controls in two concentrations. Duplicate analyses were performed.

[0145] In the second study keratinocytes from four different donors were incubated with two irritants 45 μM SDS, 60 μM SDS, 250 μM SA and 500 μM SA) 5 sensitizers (38 μM CA, 136 μM CA, 4 μM DNBS, 8 μM DNBS, 4 μM DNCB, 8 μM DNCB, 8.3 μM TMTD, 13.3 μM TMTD, 250 μM Nickel and 1500 μM Nickel) and controls in two concentrations. Duplicate analyses of each donor were performed yielding a total number of 8 samples per chemical.

[0146] The aim of the statistical analysis was to develop a classification model which allows assignment of a chemical into the group of sensitizing chemicals (A=allergen) or non-sensitizing chemicals (I=irritant). After statistical analysis of the two data sets (p<=0.05) a final list of candidate biomarkers was obtained. Each of the two data sets involved testing of chemical allergens of different sensitizing potency as well as the metal ion nickel which gave false negative results in the LLNA. Thus, the use of the methods of the present invention for assessment of new chemicals or analyzing different combinations of chemicals will contribute to a growing database of biomarker candidates. In a first approach the most appropriate candidates were top-down ranked based on increasing p-value. Table 1 shows the top 102 candidate biomarkers that were significantly influenced after exposure of keratinocytes to a set of training chemicals.

[0147] Consequently Sensitizer (A=allergen) and non-sensitizer (I=irritant) can be identified by measuring the abundance of a very limited set of gene products expressed in keratinocytes or keratinocyte cell lines:

[0148] GAPDH, TXN, LIMA1, MT1G, RPL31, ANXA3, EIF3CL;EIF3C, ARHGDIA, PCBP1, NAP1L1, HSPA1B;HSPA1A, AKR1C2, RPL14, EPS8, SERPINB2, VDAC3, ANXA1, CSTB, CLTC, EEF1A1, ANXA2, PKM2, ENO1, AHNAK, HSPA8, KRT14, UBC;UBB;RPS27A, TKT, LGALS1, PKM2, TUBB, NPM1, NME1;NME2, THBS1, LDHA, KRT5, HSPA5, TMSB10, LAMC2, KRT1, SLC25A5, ACTB, EPPK1, CFL1, LAMB3, SYNCRIP, HBG1, GSTP1, ALDOA, RPL18, EEF2, RPL4, RPL6, KRT7, HNRNPA2B1, S100A6, TDRD6, KIAA1407, HIST1H2BL, PPIA, CAP1, TUFM, SH3BGRL3, SPRR1B, ITGB4, RPL35, RPL34, S100A8, HSP90B1, HBA2;HBA1, SFN, HSP90AA1, S100A9, HSP70.1, KRT17, HSPB1, FASN, KRT6A, DSP, PRDX1, P4HB, HIST1H1E, RPL12, TUBA4A, TUBB3, YWEAG, VIM, FLNA, ANXA5, RPS28, RPLP0, LAMA3, HIST1H2AH, EIF4A1, MSN, KRT16, PGAM1, PDIA3, PPIB, LGALS7;LGALS7B, NCL, PRDX2

[0149] In a second approach linear mixed-effects models (LME) were used to account for between-donor components of variance for each biomarker in this study. LME yielded a subset of 47 protein biomarker related to sensitizer/allergen exposure and a subset of 46 biomarkers related to non-sensitizer/irritant exposure.

[0150] The list of allergen-specific biomarkers identified using LME comprises:

GAPDH, TXN, MT1G, NAP1L1, HSPA1B;HSPA1A, AKR1C2, ANXA1, EEF1A1, PKM2, LDHA, KRT5, HSPA5, ACTB, RPL18, EEF2, PPIA, S100A8, HSP90B1, HBA2;HBA1, SFN, HSP90AA1, S100A9, HSP70.1, KRT17, HSPB1, FASN, KRT6A, DSP, PRDX1, P4HB, HIST1H1E, RPL12, TUBA4A, TUBB3, YWHAG, VIM, FLNA, ANXA5, RPS28, RPLP0, LAMA3, HIST1H2AH, EIF4A1, MSN, KRT16, PGAM1, PDIA3

[0151] The list of irritant-specific biomarkers identified using LME comprises:

[0152] GAPDH, TXN, ARHGDIA, PCBP1, HSPA1B;HSPA1A, RPL14, SERPINB2, VDAC3, ANXA1, CSTB, EEF1A1, ANXA2, PKM2, ENO1, AHNAK, HSPA8, KRT14, UBC;UBB;RPS27A, TUBB, NPM1, NME1;NME2, LDHA, KRT5, TMSB10, LAMC2, KRT1, SLC25A5, CFL1, LAMB3, HBG1, GSTP1, EEF2, RPL6, KRT7, S100A6, HSP90B1, HSP70.1, KRT17, TUBA4A, RPS28, KRT16, PDIA3, PPIB, LGALS7;LGALS7B, NCL, PRDX2

Partial Least Squares--Discriminant Analysis (PLS-DA)

[0153] It is also possible to conduct a Partial Least Square Regression (PLS) analysis to select the most promising proteins by looking at the loadings scores of the two first latent components (FIG. 1). A model was built using the response variables (y) "allergen" and "irritant" and the ANOVA and LME filtered proteins as predictors (x). The first PLS components (x-axis) was plotted against the second PLS component (y-axis). Biomarkers that are close to the response variable "allergen" have a strong role in classifying chemicals as potential allergens. Biomarkers that are close to the response variable "irritant" identify chemicals as irritants. Based on the PLS loading plot (FIG. 1) the 12 most important proteins for identifying allergens comprises proteins of Group 1 (Table 1). Group 2 (Table 1) comprises proteins most important for identifying irritant/non-sensitizer.

Group 1:

[0154] GAPDH, TXN, LIMA1, MT1G, RPL31, ANXA3, EIF3CL; EIF3C, ARHGDIA, PCBP1, NAP1L1, HSPA1B; HSPA1A, AKR1C2

Group 2:

[0155] RPL14, EPS8, SERPINB2, VDAC3, ANXA1, CSTB

Group 3:

[0156] Group 3 of Table 1 contains further sensitizer biomarkers that pass the required significance criteria of p<=0.05 in at least one of the four studies that involved testing of different combinations of chemical irritants and sensitizers.

[0157] A preferred method for classification of chemicals is employing PLS analyses. FIG. 2 shows the corresponding PLS score plot of the two first principal components that are plotted against each other for all samples measured in the second study. In the score plot each point represents one 1 sample. Based on the list of 102 protein biomarkers a good separation between sensitizer and irritant treated samples was achieved. It can be seen that that samples treated with Nickel had the greatest relative distance from the centre of the plot, whereas TMTD showed a smaller distance to the centre of the plot indicating that in most samples TMTD elicited samples a smaller response.

Example 3

Targeted Biomarker Measurements

[0158] As an alternative approach to find predictive markers for sensitizing potential we measured the concentration of biomarkers using commercially available immunoassays to measure the levels of three biomarkers. The three proteins to be measured by Western Blot or ELISA were selected on the basis of a review of literature references to biomarkers of stress toxicity pathways. Cells were cultured as described in Example 1 and the cell extract was used for direct analysis by ELISA or Western Blot. All kits were used in accordance with manufacturer's instructions.

Heat Shock 70 kDa Protein 1 (HSP70, HSPA1A; HSPA1B)

[0159] Heat shock proteins (HSPs) function as molecular chaperones by preventing misfolding and aggregation of proteins essential and by assisting proper folding of proteins. The expression of HSPs is increased by heat, toxins and oxidative stress. The 70 kilodalton heat shock proteins (Hsp70s) comprise three members HSPA1A, HSPA1B, and HSPA1L. HSP70 is expressed in the skin and inhibition of HSP70 in mice using HSP70 specific antibodies resulted in a reduction in the 1-fluoro-2,4-dinitrobenzene contact hypersensitivity response (Yusuf et al. 2009). Effects of contact sensitizers and irritants on HSP70 production were determined using an HSP70-specific ELISA (Assay Designs Inc. Ann Arbor, USA). Based on the general stress response pathway implicated in the induction of HSP70 expression, it might be expected to be a marker for all classes of chemical allergens. Surprisingly, the results show that HSP70 is most strongly induced by TMTD and CA, whereas the response to DNCB, Nickel and ONCE was small, only (FIG. 3).

Metallothionein-1G (MT1G)

[0160] Metallothioneins (MTs) are low molecular weight, cysteine-rich proteins that sequester metal including Zinc and Nickel and protect cells from metal toxicity. MT expression is induced by metal ions and in oxidative stress models. Furthermore, MT appears to play cytoprotective role in mouse model for antigen-related airway inflammation (reviewed in Inoue et al. 2009). Effects of contact sensitizers and irritants on MT1G production was determined by Western Blot analysis using MT1G specific antibodies (clone UC1MT, Biozol, Eching, Germany). Surprisingly, the results showed that MT1G was most strongly induced in keratinocytes exposed to TMTD compared to the metal allergen Nickel and ONCE (FIG. 5).

Aldo-keto reductase C1 (AKR1C2)

[0161] Aldo-keto reductase family 1, member C2 (AKR1C2) is a member of the aldo/keto reductase superfamily, whose members catalyze the conversion of aldehydes and ketones to their corresponding alcohols using NADH and/or NADPH as cofactors. Upregulation of AKR1C2 gene expression has been described in dendritic cells exposed to skin sensitizers including DNBS and Nickel (Gildea et al. 2006). Effects of contact sensitizers and irritants on AKR1C2 production was determined by Western Blot analysis using AKR1C2-specific rabbit polyclonal antibodies (Antibodies-Online, Aachen, Germany). In contrast, to dendritic cells AKR1C3 was only induced in CA exposed samples (FIG. 4). These results indicate that substantial differences exist in the induction of response pathway to chemical sensitizers in dendritic cells and keratinocytes.

Example 5

Biomarker Panel for General Sensitizers

[0162] The results of Examples 1-4 have identified a panel of 102 proteins (Table 1, Groups 1-3) for the discrimination of chemical sensitizers from irritant or control chemicals. The method described to determine the panel of 102 biomarkers using reference chemicals can now be used in a revised form to test new or previously untested chemical agents to determine their potential as allergens, sensitizers or non-sensitizing. According to the present invention the method may employ measuring the concentration of biomarkers chosen from table 2 in test sets of samples exposed to new chemicals or new chemicals in combination with reference compounds as positive and negative controls. Typically, when evaluating a new test chemical the analysis should be performed using a combination of biomarkers from Table 1, especially selecting biomarkers from group 1 or group 2. Use of a panel of biomarkers selected from group 1 and group 2 will ensure the most robust discrimination between sensitizer, irritant and control. When the selected biomarkers perform well on a new chemical compound one would retain the combination of biomarkers. Alternatively it is possible test other combinations of biomarkers from group 1 or 2 in an iterative process. It is also possible to reject biomarkers from group 1 or 2 and include biomarkers from group 3. This iterative process will continue until a good classification model is produced. In certain instances higher doses of chemical sensitizers such as DNCB can as well cause skin irritation. It is thought that chemical irritants such as SDS cause skin inflammation through activation of the innate immune response.

[0163] When determining the sensitizing potential of a chemical the analysis may also involve testing of increasing exposure concentrations including irritating and non-irritating concentrations.

[0164] It is also possible to measure the irritating potential of chemical by measuring the concentration of biomarkers detailed in Table 1. Typically, the analysis should be performed using biomarkers linked to inflammatory and cellular stress processes. In particular, biomarkers selected from group 2 that are induced following exposure to SDS may be useful. This may involve but is not limited to measuring the concentration of SerpinB2 (plasminogen activator inhibitor-2, PAI-2), a serine protease inhibitor involved in cutaneous wound repair, EPS8 (epidermal growth factor receptor kinase substrate 8), a protein involved in actin remodelling and CTSB (Cystatin B), an intracellular inhibitor of cystein proteases. Of particular value to the present invention is ANXA1 (Annexin 1) a plasma membrane associated protein involved inflammatory processes. Other markers for irritants include VDAC3 (Voltage-dependent anion-selective channel protein 3), a pore-forming proteins mainly located in the mitochondrial outer membrane, and RPL14 (60S ribosomal protein L14). The inclusion and combination of proteins modulated by sensitizing or irritating chemicals will allow to correctly predict the sensitizing or irritating potential of new chemicals.

Example 6

Biomarker Panel for Contact Sensitizers

[0165] Within the panel of general markers of sensitizing potential it is also possible to select the strongest discriminant markers correlating with contact sensitizer effect. Using PLS-DA a sub-group of 12 proteins providing the strongest separation of skin sensitizers from all other classes was identified (Table 1, Group 1). It was thus possible to perform a targeted analysis to measure just these 12 proteins to detect known skin sensitizers and demonstrate whether an unknown test chemical or combination of chemicals possesses skin sensitizing potential.

Example 7

Selective Reaction Monitoring (SRM) Assays for the Multiplexed Analysis of Biomarkers

[0166] To approach the complex and variable cellular response to different chemical sensitizers, assays are required that allow simultaneous analysis of several biomarkers representing different cellular response pathways. SRM-based approaches are an attractive alternative to ELISAs due to the sensitivity and selectivity of the technique, the capacity to multiplex and the limited availability of antibodies. Here, signature peptides unique to the protein of interest are measured to provide quantitative information of that protein in the sample. Changes in peptide abundance in response to chemical exposure experiments can be determined using typical isotopic TMT-SRM workflows. Here, quantitation is based on the relative MS intensities of the sample peptide labelled with TMTzero versus an internal reference sample labelled with TMTsixplex heavy isotope. Four proteins were selected to develop multiplexed SRM assays: Thymosin beta 10 (TYB10), Protein S100-A8 (3100A8), Protein S100-A9 (S100A9) and Heat shock cognate 71 kDa protein (HSPA8).

Methods

Selection of Candidate Peptides for SRM Quantitation

[0167] Using existing MS/MS data, most frequently observed specific peptides were selected for quantitation. If possible at least three peptides per protein were selected for SRM development. The representative peptides for the four selected proteins (HSPA8, S100A8, S100A9 and TYB10) are shown in Table 5 (FIG. 9). Criteria for selection included; no missed cleavages with trypsin and no variable modifications (in-vivo or experimental).

Preparation of Samples

[0168] Keratinocyte samples are treated with sensitizer and irritant or are left untreated as in the discovery phase. A pool sample is digested with trypsin and labelled with TMTsixplex to produce the heavy-labelled version of peptides to act as a reference for quantitation. Test samples are digested and labelled with TMTzero to produce the light labelled version of peptides. 15 μg each of the pool and test sample are afterwards mixed and undergo subsequent purification by solid-phase extraction and strong cation exchange using volatile buffers.

SRM Analysis of Samples

[0169] The mixed heavy and light labelled samples are resuspended in 5% Acetonitril (=ACN), 0.2% Formic acid (=FA) and infused into an Accela 1250 Liquid Chromatography (LC) system coupled to a TSQ Vantage triple stage quadrupole mass spectrometer (Thermo Fisher) and SRM data are acquired. Corresponding TMTsixplex-labelled and TMTzero-labelled fragment ion masses are calculated and MS instrument parameters optimised for individual Q1 and Q3 transition pairs. A pooled cell lysate sample is digested, labelled with TMTsixplex and combined with the TMTzero-labelled test sample. Using accurate retention times for each peptide, the SRM cycle time is 1.5 seconds with retention time windows used to maximise the scan time given to each SRM transition. Including washes and time to equalibrate the column, the total run time of the method is 23 minutes. Declustering voltage is set to 5 Volt, Peak width (FWHM) is set to 0.5 and Chrome filter Peak width is set to 6 seconds. Specific parameters for the SRM transitions are listed in Table 5 (FIG. 9).

Data Analysis

[0170] SRMs are visualised through Skyline version 1.2.0.3425 (https://skyline.gs.washington.edu/labkey/project/home/software/Skyline/b- egin.view) and all peak matching visually verified. Integrated peak areas are exported into Microsoft Excel. Transitions are summed to give a total intensity for all transitions for each peptide. The amount of endogenous (light) peptide is calculated based on the peak area ratio relative to the internal heavy-labelled reference sample.

REFERENCES

[0171] Corsini E, Mitjans M, Galbiati V, Lucchi L, Galli C L, Marinovich M (2009). Use of IL-18 production in a human keratinocyte cell line to discriminate contact sensitizers from irritants and low molecular weight respiratory allergens. Toxicol In Vitro. 23(5):789-96.

[0172] Emter R, Ellis G, Natsch A (2010). Performance of a novel keratinocyte-based reporter cell line to screen skin sensitizers in vitro. Toxicol Appl Pharmacol. 245(3):281-90.

[0173] Gildea L A, Ryan C A, Foertsch L M, Kennedy J M, Dearman R J, Kimber I, Gerberick G F. (2006) Identification of gene expression changes induced by chemical allergens in dendritic cells: opportunities for skin sensitization testing. J Invest Dermatol. 126(8):1813-22.

[0174] Inoue K, Takano H, Shimada A, Satoh M (2009). Metallothionein as an anti-inflammatory mediator. Mediators Inflamm. 2009:101659.

[0175] Kimber, I., Hilton, J., Dearman, R. J., Gerberick, G. F., Ryan, C. A., Basketter, D. A., Scholes, E. W., Ladics, G. S., Loveless, S. E., House, R. V., Guy, A., (1995). An international evaluation of the murine local lymph node assay and comparison of modified procedures. Toxicology 103, 63-73.

[0176] Magnusson, B., Kligman, A. M., (1969). The identification of contact allergens by animal assay. The guinea pig maximization test. J. Invest. Dermatol. 52, 268-276.

[0177] Natsch A, Emter R (2008). Skin sensitizers induce antioxidant response element dependent genes: application to the in vitro testing of the sensitization potential of chemicals. Toxicol Sci. 102(1):110-9.

[0178] Natsch A. (2010). The Nrf2-Keap1-ARE toxicity pathway as a cellular sensor for skin sensitizers--functional relevance and a hypothesis on innate reactions to skin sensitizers. Toxicol Sci. 113:284-92.

[0179] Vandebriel R J, Pennings J L, Baken K A, Pronk T E, Boorsma A, Gottschalk R, Van Loveren H (2010). Keratinocyte gene expression profiles discriminate sensitizing and irritating compounds. Toxicol Sci. 2010 117(1):81-9.

[0180] Van Och F M, Van Loveren H, Van Wolfswinkel J C, Machielsen A J, Vandebriel R J (2005). Assessment of potency of allergenic activity of low molecular weight compounds based on IL-1alpha and IL-18 production by a murine and human keratinocyte cell line. Toxicology. 210(2-3):95-109.

[0181] Yoshikawa Y, Sasahara Y, Kitano Y, Kanazawa N, Shima H, Hashimoto-Tamaoki T (2010). Upregulation of genes orchestrating keratinocyte differentiation, including the novel marker gene ID2, by contact sensitizers in human bulge-derived keratinocytes. J Biochem Mol Toxicol. 24(1):10-20.

[0182] Yusuf N, Nasti T H, Huang C M, Huber B S, Jaleel T, Lin H Y, Xu H, Elmets C A (2009). Heat shock proteins HSP27 and HSP70 are present in the skin and are important mediators of allergic contact hypersensitivity. J Immunol. 182(1):675-83.

[0183] Kimber I, Basketter D A, McFadden J P, Dearman R J (2011). Characterization of skin sensitizing chemicals: a lesson learnt from nickel allergy. J Immunotoxicol. (1):1-2.

Sequence CWU 1

1

1081335PRTHomo sapiens 1Met Gly Lys Val Lys Val Gly Val Asn Gly Phe Gly Arg Ile Gly Arg 1 5 10 15 Leu Val Thr Arg Ala Ala Phe Asn Ser Gly Lys Val Asp Ile Val Ala 20 25 30 Ile Asn Asp Pro Phe Ile Asp Leu Asn Tyr Met Val Tyr Met Phe Gln 35 40 45 Tyr Asp Ser Thr His Gly Lys Phe His Gly Thr Val Lys Ala Glu Asn 50 55 60 Gly Lys Leu Val Ile Asn Gly Asn Pro Ile Thr Ile Phe Gln Glu Arg 65 70 75 80 Asp Pro Ser Lys Ile Lys Trp Gly Asp Ala Gly Ala Glu Tyr Val Val 85 90 95 Glu Ser Thr Gly Val Phe Thr Thr Met Glu Lys Ala Gly Ala His Leu 100 105 110 Gln Gly Gly Ala Lys Arg Val Ile Ile Ser Ala Pro Ser Ala Asp Ala 115 120 125 Pro Met Phe Val Met Gly Val Asn His Glu Lys Tyr Asp Asn Ser Leu 130 135 140 Lys Ile Ile Ser Asn Ala Ser Cys Thr Thr Asn Cys Leu Ala Pro Leu 145 150 155 160 Ala Lys Val Ile His Asp Asn Phe Gly Ile Val Glu Gly Leu Met Thr 165 170 175 Thr Val His Ala Ile Thr Ala Thr Gln Lys Thr Val Asp Gly Pro Ser 180 185 190 Gly Lys Leu Trp Arg Asp Gly Arg Gly Ala Leu Gln Asn Ile Ile Pro 195 200 205 Ala Ser Thr Gly Ala Ala Lys Ala Val Gly Lys Val Ile Pro Glu Leu 210 215 220 Asn Gly Lys Leu Thr Gly Met Ala Phe Arg Val Pro Thr Ala Asn Val 225 230 235 240 Ser Val Val Asp Leu Thr Cys Arg Leu Glu Lys Pro Ala Lys Tyr Asp 245 250 255 Asp Ile Lys Lys Val Val Lys Gln Ala Ser Glu Gly Pro Leu Lys Gly 260 265 270 Ile Leu Gly Tyr Thr Glu His Gln Val Val Ser Ser Asp Phe Asn Ser 275 280 285 Asp Thr His Ser Ser Thr Phe Asp Ala Gly Ala Gly Ile Ala Leu Asn 290 295 300 Asp His Phe Val Lys Leu Ile Ser Trp Tyr Asp Asn Glu Phe Gly Tyr 305 310 315 320 Ser Asn Arg Val Val Asp Leu Met Ala His Met Ala Ser Lys Glu 325 330 335 2105PRTHomo sapiens 2Met Val Lys Gln Ile Glu Ser Lys Thr Ala Phe Gln Glu Ala Leu Asp 1 5 10 15 Ala Ala Gly Asp Lys Leu Val Val Val Asp Phe Ser Ala Thr Trp Cys 20 25 30 Gly Pro Cys Lys Met Ile Lys Pro Phe Phe His Ser Leu Ser Glu Lys 35 40 45 Tyr Ser Asn Val Ile Phe Leu Glu Val Asp Val Asp Asp Cys Gln Asp 50 55 60 Val Ala Ser Glu Cys Glu Val Lys Cys Met Pro Thr Phe Gln Phe Phe 65 70 75 80 Lys Lys Gly Gln Lys Val Gly Glu Phe Ser Gly Ala Asn Lys Glu Lys 85 90 95 Leu Glu Ala Thr Ile Asn Glu Leu Val 100 105 3759PRTHomo sapiens 3Met Glu Ser Ser Pro Phe Asn Arg Arg Gln Trp Thr Ser Leu Ser Leu 1 5 10 15 Arg Val Thr Ala Lys Glu Leu Ser Leu Val Asn Lys Asn Lys Ser Ser 20 25 30 Ala Ile Val Glu Ile Phe Ser Lys Tyr Gln Lys Ala Ala Glu Glu Thr 35 40 45 Asn Met Glu Lys Lys Arg Ser Asn Thr Glu Asn Leu Ser Gln His Phe 50 55 60 Arg Lys Gly Thr Leu Thr Val Leu Lys Lys Lys Trp Glu Asn Pro Gly 65 70 75 80 Leu Gly Ala Glu Ser His Thr Asp Ser Leu Arg Asn Ser Ser Thr Glu 85 90 95 Ile Arg His Arg Ala Asp His Pro Pro Ala Glu Val Thr Ser His Ala 100 105 110 Ala Ser Gly Ala Lys Ala Asp Gln Glu Glu Gln Ile His Pro Arg Ser 115 120 125 Arg Leu Arg Ser Pro Pro Glu Ala Leu Val Gln Gly Arg Tyr Pro His 130 135 140 Ile Lys Asp Gly Glu Asp Leu Lys Asp His Ser Thr Glu Ser Lys Lys 145 150 155 160 Met Glu Asn Cys Leu Gly Glu Ser Arg His Glu Val Glu Lys Ser Glu 165 170 175 Ile Ser Glu Asn Thr Asp Ala Ser Gly Lys Ile Glu Lys Tyr Asn Val 180 185 190 Pro Leu Asn Arg Leu Lys Met Met Phe Glu Lys Gly Glu Pro Thr Gln 195 200 205 Thr Lys Ile Leu Arg Ala Gln Ser Arg Ser Ala Ser Gly Arg Lys Ile 210 215 220 Ser Glu Asn Ser Tyr Ser Leu Asp Asp Leu Glu Ile Gly Pro Gly Gln 225 230 235 240 Leu Ser Ser Ser Thr Phe Asp Ser Glu Lys Asn Glu Ser Arg Arg Asn 245 250 255 Leu Glu Leu Pro Arg Leu Ser Glu Thr Ser Ile Lys Asp Arg Met Ala 260 265 270 Lys Tyr Gln Ala Ala Val Ser Lys Gln Ser Ser Ser Thr Asn Tyr Thr 275 280 285 Asn Glu Leu Lys Ala Ser Gly Gly Glu Ile Lys Ile His Lys Met Glu 290 295 300 Gln Lys Glu Asn Val Pro Pro Gly Pro Glu Val Cys Ile Thr His Gln 305 310 315 320 Glu Gly Glu Lys Ile Ser Ala Asn Glu Asn Ser Leu Ala Val Arg Ser 325 330 335 Thr Pro Ala Glu Asp Asp Ser Arg Asp Ser Gln Val Lys Ser Glu Val 340 345 350 Gln Gln Pro Val His Pro Lys Pro Leu Ser Pro Asp Ser Arg Ala Ser 355 360 365 Ser Leu Ser Glu Ser Ser Pro Pro Lys Ala Met Lys Lys Phe Gln Ala 370 375 380 Pro Ala Arg Glu Thr Cys Val Glu Cys Gln Lys Thr Val Tyr Pro Met 385 390 395 400 Glu Arg Leu Leu Ala Asn Gln Gln Val Phe His Ile Ser Cys Phe Arg 405 410 415 Cys Ser Tyr Cys Asn Asn Lys Leu Ser Leu Gly Thr Tyr Ala Ser Leu 420 425 430 His Gly Arg Ile Tyr Cys Lys Pro His Phe Asn Gln Leu Phe Lys Ser 435 440 445 Lys Gly Asn Tyr Asp Glu Gly Phe Gly His Arg Pro His Lys Asp Leu 450 455 460 Trp Ala Ser Lys Asn Glu Asn Glu Glu Ile Leu Glu Arg Pro Ala Gln 465 470 475 480 Leu Ala Asn Ala Arg Glu Thr Pro His Ser Pro Gly Val Glu Asp Ala 485 490 495 Pro Ile Ala Lys Val Gly Val Leu Ala Ala Ser Met Glu Ala Lys Ala 500 505 510 Ser Ser Gln Gln Glu Lys Glu Asp Lys Pro Ala Glu Thr Lys Lys Leu 515 520 525 Arg Ile Ala Trp Pro Pro Pro Thr Glu Leu Gly Ser Ser Gly Ser Ala 530 535 540 Leu Glu Glu Gly Ile Lys Met Ser Lys Pro Lys Trp Pro Pro Glu Asp 545 550 555 560 Glu Ile Ser Lys Pro Glu Val Pro Glu Asp Val Asp Leu Asp Leu Lys 565 570 575 Lys Leu Arg Arg Ser Ser Ser Leu Lys Glu Arg Ser Arg Pro Phe Thr 580 585 590 Val Ala Ala Ser Phe Gln Ser Thr Ser Val Lys Ser Pro Lys Thr Val 595 600 605 Ser Pro Pro Ile Arg Lys Gly Trp Ser Met Ser Glu Gln Ser Glu Glu 610 615 620 Ser Val Gly Gly Arg Val Ala Glu Arg Lys Gln Val Glu Asn Ala Lys 625 630 635 640 Ala Ser Lys Lys Asn Gly Asn Val Gly Lys Thr Thr Trp Gln Asn Lys 645 650 655 Glu Ser Lys Gly Glu Thr Gly Lys Arg Ser Lys Glu Gly His Ser Leu 660 665 670 Glu Met Glu Asn Glu Asn Leu Val Glu Asn Gly Ala Asp Ser Asp Glu 675 680 685 Asp Asp Asn Ser Phe Leu Lys Gln Gln Ser Pro Gln Glu Pro Lys Ser 690 695 700 Leu Asn Trp Ser Ser Phe Val Asp Asn Thr Phe Ala Glu Glu Phe Thr 705 710 715 720 Thr Gln Asn Gln Lys Ser Gln Asp Val Glu Leu Trp Glu Gly Glu Val 725 730 735 Val Lys Glu Leu Ser Val Glu Glu Gln Ile Lys Arg Asn Arg Tyr Tyr 740 745 750 Asp Glu Asp Glu Asp Glu Glu 755 462PRTHomo sapiens 4Met Asp Pro Asn Cys Ser Cys Ala Ala Ala Gly Val Ser Cys Thr Cys 1 5 10 15 Ala Ser Ser Cys Lys Cys Lys Glu Cys Lys Cys Thr Ser Cys Lys Lys 20 25 30 Ser Cys Cys Ser Cys Cys Pro Val Gly Cys Ala Lys Cys Ala Gln Gly 35 40 45 Cys Ile Cys Lys Gly Ala Ser Glu Lys Cys Ser Cys Cys Ala 50 55 60 5125PRTHomo sapiens 5Met Ala Pro Ala Lys Lys Gly Gly Glu Lys Lys Lys Gly Arg Ser Ala 1 5 10 15 Ile Asn Glu Val Val Thr Arg Glu Tyr Thr Ile Asn Ile His Lys Arg 20 25 30 Ile His Gly Val Gly Phe Lys Lys Arg Ala Pro Arg Ala Leu Lys Glu 35 40 45 Ile Arg Lys Phe Ala Met Lys Glu Met Gly Thr Pro Asp Val Arg Ile 50 55 60 Asp Thr Arg Leu Asn Lys Ala Val Trp Ala Lys Gly Ile Arg Asn Val 65 70 75 80 Pro Tyr Arg Ile Arg Val Arg Leu Ser Arg Lys Arg Asn Glu Asp Glu 85 90 95 Asp Ser Pro Asn Lys Leu Tyr Thr Leu Val Thr Tyr Val Pro Val Thr 100 105 110 Thr Phe Lys Asn Leu Gln Thr Val Asn Val Asp Glu Asn 115 120 125 6323PRTHomo sapiens 6Met Ala Ser Ile Trp Val Gly His Arg Gly Thr Val Arg Asp Tyr Pro 1 5 10 15 Asp Phe Ser Pro Ser Val Asp Ala Glu Ala Ile Gln Lys Ala Ile Arg 20 25 30 Gly Ile Gly Thr Asp Glu Lys Met Leu Ile Ser Ile Leu Thr Glu Arg 35 40 45 Ser Asn Ala Gln Arg Gln Leu Ile Val Lys Glu Tyr Gln Ala Ala Tyr 50 55 60 Gly Lys Glu Leu Lys Asp Asp Leu Lys Gly Asp Leu Ser Gly His Phe 65 70 75 80 Glu His Leu Met Val Ala Leu Val Thr Pro Pro Ala Val Phe Asp Ala 85 90 95 Lys Gln Leu Lys Lys Ser Met Lys Gly Ala Gly Thr Asn Glu Asp Ala 100 105 110 Leu Ile Glu Ile Leu Thr Thr Arg Thr Ser Arg Gln Met Lys Asp Ile 115 120 125 Ser Gln Ala Tyr Tyr Thr Val Tyr Lys Lys Ser Leu Gly Asp Asp Ile 130 135 140 Ser Ser Glu Thr Ser Gly Asp Phe Arg Lys Ala Leu Leu Thr Leu Ala 145 150 155 160 Asp Gly Arg Arg Asp Glu Ser Leu Lys Val Asp Glu His Leu Ala Lys 165 170 175 Gln Asp Ala Gln Ile Leu Tyr Lys Ala Gly Glu Asn Arg Trp Gly Thr 180 185 190 Asp Glu Asp Lys Phe Thr Glu Ile Leu Cys Leu Arg Ser Phe Pro Gln 195 200 205 Leu Lys Leu Thr Phe Asp Glu Tyr Arg Asn Ile Ser Gln Lys Asp Ile 210 215 220 Val Asp Ser Ile Lys Gly Glu Leu Ser Gly His Phe Glu Asp Leu Leu 225 230 235 240 Leu Ala Ile Val Asn Cys Val Arg Asn Thr Pro Ala Phe Leu Ala Glu 245 250 255 Arg Leu His Arg Ala Leu Lys Gly Ile Gly Thr Asp Glu Phe Thr Leu 260 265 270 Asn Arg Ile Met Val Ser Arg Ser Glu Ile Asp Leu Leu Asp Ile Arg 275 280 285 Thr Glu Phe Lys Lys His Tyr Gly Tyr Ser Leu Tyr Ser Ala Ile Lys 290 295 300 Ser Asp Thr Ser Gly Asp Tyr Glu Ile Thr Leu Leu Lys Ile Cys Gly 305 310 315 320 Gly Asp Asp 7913PRTHomo sapiens 7Met Ser Arg Phe Phe Thr Thr Gly Ser Asp Ser Glu Ser Glu Ser Ser 1 5 10 15 Leu Ser Gly Glu Glu Leu Val Thr Lys Pro Val Gly Gly Asn Tyr Gly 20 25 30 Lys Gln Pro Leu Leu Leu Ser Glu Asp Glu Glu Asp Thr Lys Arg Val 35 40 45 Val Arg Ser Ala Lys Asp Lys Arg Phe Glu Glu Leu Thr Asn Leu Ile 50 55 60 Arg Thr Ile Arg Asn Ala Met Lys Ile Arg Asp Val Thr Lys Cys Leu 65 70 75 80 Glu Glu Phe Glu Leu Leu Gly Lys Ala Tyr Gly Lys Ala Lys Ser Ile 85 90 95 Val Asp Lys Glu Gly Val Pro Arg Phe Tyr Ile Arg Ile Leu Ala Asp 100 105 110 Leu Glu Asp Tyr Leu Asn Glu Leu Trp Glu Asp Lys Glu Gly Lys Lys 115 120 125 Lys Met Asn Lys Asn Asn Ala Lys Ala Leu Ser Thr Leu Arg Gln Lys 130 135 140 Ile Arg Lys Tyr Asn Arg Asp Phe Glu Ser His Ile Thr Ser Tyr Lys 145 150 155 160 Gln Asn Pro Glu Gln Ser Ala Asp Glu Asp Ala Glu Lys Asn Glu Glu 165 170 175 Asp Ser Glu Gly Ser Ser Asp Glu Asp Glu Asp Glu Asp Gly Val Ser 180 185 190 Ala Ala Thr Phe Leu Lys Lys Lys Ser Glu Ala Pro Ser Gly Glu Ser 195 200 205 Arg Lys Phe Leu Lys Lys Met Asp Asp Glu Asp Glu Asp Ser Glu Asp 210 215 220 Ser Glu Asp Asp Glu Asp Trp Asp Thr Gly Ser Thr Ser Ser Asp Ser 225 230 235 240 Asp Ser Glu Glu Glu Glu Gly Lys Gln Thr Ala Leu Ala Ser Arg Phe 245 250 255 Leu Lys Lys Ala Pro Thr Thr Asp Glu Asp Lys Lys Ala Ala Glu Lys 260 265 270 Lys Arg Glu Asp Lys Ala Lys Lys Lys His Asp Arg Lys Ser Lys Arg 275 280 285 Leu Asp Glu Glu Glu Glu Asp Asn Glu Gly Gly Glu Trp Glu Arg Val 290 295 300 Arg Gly Gly Val Pro Leu Val Lys Glu Lys Pro Lys Met Phe Ala Lys 305 310 315 320 Gly Thr Glu Ile Thr His Ala Val Val Ile Lys Lys Leu Asn Glu Ile 325 330 335 Leu Gln Ala Arg Gly Lys Lys Gly Thr Asp Arg Ala Ala Gln Ile Glu 340 345 350 Leu Leu Gln Leu Leu Val Gln Ile Ala Ala Glu Asn Asn Leu Gly Glu 355 360 365 Gly Val Ile Val Lys Ile Lys Phe Asn Ile Ile Ala Ser Leu Tyr Asp 370 375 380 Tyr Asn Pro Asn Leu Ala Thr Tyr Met Lys Pro Glu Met Trp Gly Lys 385 390 395 400 Cys Leu Asp Cys Ile Asn Glu Leu Met Asp Ile Leu Phe Ala Asn Pro 405 410 415 Asn Ile Phe Val Gly Glu Asn Ile Leu Glu Glu Ser Glu Asn Leu His 420 425 430 Asn Ala Asp Gln Pro Leu Arg Val Arg Gly Cys Ile Leu Thr Leu Val 435 440 445 Glu Arg Met Asp Glu Glu Phe Thr Lys Ile Met Gln Asn Thr Asp Pro 450 455 460 His Ser Gln Glu Tyr Val Glu His Leu Lys Asp Glu Ala Gln Val Cys 465 470 475 480 Ala Ile Ile Glu Arg Val Gln Arg Tyr Leu Glu Glu Lys Gly Thr Thr 485 490 495 Glu Glu Val Cys Arg Ile Tyr Leu Leu Arg Ile Leu His Thr Tyr Tyr 500 505 510 Lys Phe Asp Tyr Lys Ala His Gln Arg Gln Leu Thr Pro Pro Glu Gly 515 520 525 Ser Ser Lys Ser Glu Gln Asp Gln Ala Glu Asn Glu Gly Glu Asp Ser 530 535 540 Ala Val Leu Met Glu Arg Leu Cys Lys Tyr Ile Tyr Ala Lys Asp Arg 545 550 555 560 Thr Asp Arg Ile Arg Thr Cys Ala Ile Leu Cys His Ile Tyr His His 565 570 575 Ala Leu His Ser Arg Trp Tyr Gln

Ala Arg Asp Leu Met Leu Met Ser 580 585 590 His Leu Gln Asp Asn Ile Gln His Ala Asp Pro Pro Val Gln Ile Leu 595 600 605 Tyr Asn Arg Thr Met Val Gln Leu Gly Ile Cys Ala Phe Arg Gln Gly 610 615 620 Leu Thr Lys Asp Ala His Asn Ala Leu Leu Asp Ile Gln Ser Ser Gly 625 630 635 640 Arg Ala Lys Glu Leu Leu Gly Gln Gly Leu Leu Leu Arg Ser Leu Gln 645 650 655 Glu Arg Asn Gln Glu Gln Glu Lys Val Glu Arg Arg Arg Gln Val Pro 660 665 670 Phe His Leu His Ile Asn Leu Glu Leu Leu Glu Cys Val Tyr Leu Val 675 680 685 Ser Ala Met Leu Leu Glu Ile Pro Tyr Met Ala Ala His Glu Ser Asp 690 695 700 Ala Arg Arg Arg Met Ile Ser Lys Gln Phe His His Gln Leu Arg Val 705 710 715 720 Gly Glu Arg Gln Pro Leu Leu Gly Pro Pro Glu Ser Met Arg Glu His 725 730 735 Val Val Ala Ala Ser Lys Ala Met Lys Met Gly Asp Trp Lys Thr Cys 740 745 750 His Ser Phe Ile Ile Asn Glu Lys Met Asn Gly Lys Val Trp Asp Leu 755 760 765 Phe Pro Glu Ala Asp Lys Val Arg Thr Met Leu Val Arg Lys Ile Gln 770 775 780 Glu Glu Ser Leu Arg Thr Tyr Leu Phe Thr Tyr Ser Ser Val Tyr Asp 785 790 795 800 Ser Ile Ser Met Glu Thr Leu Ser Asp Met Phe Glu Leu Asp Leu Pro 805 810 815 Thr Val His Ser Ile Ile Ser Lys Met Ile Ile Asn Glu Glu Leu Met 820 825 830 Ala Ser Leu Asp Gln Pro Thr Gln Thr Val Val Met His Arg Thr Glu 835 840 845 Pro Thr Ala Gln Gln Asn Leu Ala Leu Gln Leu Ala Glu Lys Leu Gly 850 855 860 Ser Leu Val Glu Asn Asn Glu Arg Val Phe Asp His Lys Gln Gly Thr 865 870 875 880 Tyr Gly Gly Tyr Phe Arg Asp Gln Lys Asp Gly Tyr Arg Lys Asn Glu 885 890 895 Gly Tyr Met Arg Arg Gly Gly Tyr Arg Gln Gln Gln Ser Gln Thr Ala 900 905 910 Tyr 8204PRTHomo sapiens 8Met Ala Glu Gln Glu Pro Thr Ala Glu Gln Leu Ala Gln Ile Ala Ala 1 5 10 15 Glu Asn Glu Glu Asp Glu His Ser Val Asn Tyr Lys Pro Pro Ala Gln 20 25 30 Lys Ser Ile Gln Glu Ile Gln Glu Leu Asp Lys Asp Asp Glu Ser Leu 35 40 45 Arg Lys Tyr Lys Glu Ala Leu Leu Gly Arg Val Ala Val Ser Ala Asp 50 55 60 Pro Asn Val Pro Asn Val Val Val Thr Gly Leu Thr Leu Val Cys Ser 65 70 75 80 Ser Ala Pro Gly Pro Leu Glu Leu Asp Leu Thr Gly Asp Leu Glu Ser 85 90 95 Phe Lys Lys Gln Ser Phe Val Leu Lys Glu Gly Val Glu Tyr Arg Ile 100 105 110 Lys Ile Ser Phe Arg Val Asn Arg Glu Ile Val Ser Gly Met Lys Tyr 115 120 125 Ile Gln His Thr Tyr Arg Lys Gly Val Lys Ile Asp Lys Thr Asp Tyr 130 135 140 Met Val Gly Ser Tyr Gly Pro Arg Ala Glu Glu Tyr Glu Phe Leu Thr 145 150 155 160 Pro Val Glu Glu Ala Pro Lys Gly Met Leu Ala Arg Gly Ser Tyr Ser 165 170 175 Ile Lys Ser Arg Phe Thr Asp Asp Asp Lys Thr Asp His Leu Ser Trp 180 185 190 Glu Trp Asn Leu Thr Ile Lys Lys Asp Trp Lys Asp 195 200 9 356PRTHomo sapiens 9Met Asp Ala Gly Val Thr Glu Ser Gly Leu Asn Val Thr Leu Thr Ile 1 5 10 15 Arg Leu Leu Met His Gly Lys Glu Val Gly Ser Ile Ile Gly Lys Lys 20 25 30 Gly Glu Ser Val Lys Arg Ile Arg Glu Glu Ser Gly Ala Arg Ile Asn 35 40 45 Ile Ser Glu Gly Asn Cys Pro Glu Arg Ile Ile Thr Leu Thr Gly Pro 50 55 60 Thr Asn Ala Ile Phe Lys Ala Phe Ala Met Ile Ile Asp Lys Leu Glu 65 70 75 80 Glu Asp Ile Asn Ser Ser Met Thr Asn Ser Thr Ala Ala Ser Arg Pro 85 90 95 Pro Val Thr Leu Arg Leu Val Val Pro Ala Thr Gln Cys Gly Ser Leu 100 105 110 Ile Gly Lys Gly Gly Cys Lys Ile Lys Glu Ile Arg Glu Ser Thr Gly 115 120 125 Ala Gln Val Gln Val Ala Gly Asp Met Leu Pro Asn Ser Thr Glu Arg 130 135 140 Ala Ile Thr Ile Ala Gly Val Pro Gln Ser Val Thr Glu Cys Val Lys 145 150 155 160 Gln Ile Cys Leu Val Met Leu Glu Thr Leu Ser Gln Ser Pro Gln Gly 165 170 175 Arg Val Met Thr Ile Pro Tyr Gln Pro Met Pro Ala Ser Ser Pro Val 180 185 190 Ile Cys Ala Gly Gly Gln Asp Arg Cys Ser Asp Ala Ala Gly Tyr Pro 195 200 205 His Ala Thr His Asp Leu Glu Gly Pro Pro Leu Asp Ala Tyr Ser Ile 210 215 220 Gln Gly Gln His Thr Ile Ser Pro Leu Asp Leu Ala Lys Leu Asn Gln 225 230 235 240 Val Ala Arg Gln Gln Ser His Phe Ala Met Met His Gly Gly Thr Gly 245 250 255 Phe Ala Gly Ile Asp Ser Ser Ser Pro Glu Val Lys Gly Tyr Trp Ala 260 265 270 Ser Leu Asp Ala Ser Thr Gln Thr Thr His Glu Leu Thr Ile Pro Asn 275 280 285 Asn Leu Ile Gly Cys Ile Ile Gly Arg Gln Gly Ala Asn Ile Asn Glu 290 295 300 Ile Arg Gln Met Ser Gly Ala Gln Ile Lys Ile Ala Asn Pro Val Glu 305 310 315 320 Gly Ser Ser Gly Arg Gln Val Thr Ile Thr Gly Ser Ala Ala Ser Ile 325 330 335 Ser Leu Ala Gln Tyr Leu Ile Asn Ala Arg Leu Ser Ser Glu Lys Gly 340 345 350 Met Gly Cys Ser 355 10391PRTHomo sapiens 10Met Ala Asp Ile Asp Asn Lys Glu Gln Ser Glu Leu Asp Gln Asp Leu 1 5 10 15 Asp Asp Val Glu Glu Val Glu Glu Glu Glu Thr Gly Glu Glu Thr Lys 20 25 30 Leu Lys Ala Arg Gln Leu Thr Val Gln Met Met Gln Asn Pro Gln Ile 35 40 45 Leu Ala Ala Leu Gln Glu Arg Leu Asp Gly Leu Val Glu Thr Pro Thr 50 55 60 Gly Tyr Ile Glu Ser Leu Pro Arg Val Val Lys Arg Arg Val Asn Ala 65 70 75 80 Leu Lys Asn Leu Gln Val Lys Cys Ala Gln Ile Glu Ala Lys Phe Tyr 85 90 95 Glu Glu Val His Asp Leu Glu Arg Lys Tyr Ala Val Leu Tyr Gln Pro 100 105 110 Leu Phe Asp Lys Arg Phe Glu Ile Ile Asn Ala Ile Tyr Glu Pro Thr 115 120 125 Glu Glu Glu Cys Glu Trp Lys Pro Asp Glu Glu Asp Glu Ile Ser Glu 130 135 140 Glu Leu Lys Glu Lys Ala Lys Ile Glu Asp Glu Lys Lys Asp Glu Glu 145 150 155 160 Lys Glu Asp Pro Lys Gly Ile Pro Glu Phe Trp Leu Thr Val Phe Lys 165 170 175 Asn Val Asp Leu Leu Ser Asp Met Val Gln Glu His Asp Glu Pro Ile 180 185 190 Leu Lys His Leu Lys Asp Ile Lys Val Lys Phe Ser Asp Ala Gly Gln 195 200 205 Pro Met Ser Phe Val Leu Glu Phe His Phe Glu Pro Asn Glu Tyr Phe 210 215 220 Thr Asn Glu Val Leu Thr Lys Thr Tyr Arg Met Arg Ser Glu Pro Asp 225 230 235 240 Asp Ser Asp Pro Phe Ser Phe Asp Gly Pro Glu Ile Met Gly Cys Thr 245 250 255 Gly Cys Gln Ile Asp Trp Lys Lys Gly Lys Asn Val Thr Leu Lys Thr 260 265 270 Ile Lys Lys Lys Gln Lys His Lys Gly Arg Gly Thr Val Arg Thr Val 275 280 285 Thr Lys Thr Val Ser Asn Asp Ser Phe Phe Asn Phe Phe Ala Pro Pro 290 295 300 Glu Val Pro Glu Ser Gly Asp Leu Asp Asp Asp Ala Glu Ala Ile Leu 305 310 315 320 Ala Ala Asp Phe Glu Ile Gly His Phe Leu Arg Glu Arg Ile Ile Pro 325 330 335 Arg Ser Val Leu Tyr Phe Thr Gly Glu Ala Ile Glu Asp Asp Asp Asp 340 345 350 Asp Tyr Asp Glu Glu Gly Glu Glu Ala Asp Glu Glu Gly Glu Glu Glu 355 360 365 Gly Asp Glu Glu Asn Asp Pro Asp Tyr Asp Pro Lys Lys Asp Gln Asn 370 375 380 Pro Ala Glu Cys Lys Gln Gln 385 390 11641PRTHomo sapiens 11Met Ala Lys Ala Ala Ala Ile Gly Ile Asp Leu Gly Thr Thr Tyr Ser 1 5 10 15 Cys Val Gly Val Phe Gln His Gly Lys Val Glu Ile Ile Ala Asn Asp 20 25 30 Gln Gly Asn Arg Thr Thr Pro Ser Tyr Val Ala Phe Thr Asp Thr Glu 35 40 45 Arg Leu Ile Gly Asp Ala Ala Lys Asn Gln Val Ala Leu Asn Pro Gln 50 55 60 Asn Thr Val Phe Asp Ala Lys Arg Leu Ile Gly Arg Lys Phe Gly Asp 65 70 75 80 Pro Val Val Gln Ser Asp Met Lys His Trp Pro Phe Gln Val Ile Asn 85 90 95 Asp Gly Asp Lys Pro Lys Val Gln Val Ser Tyr Lys Gly Glu Thr Lys 100 105 110 Ala Phe Tyr Pro Glu Glu Ile Ser Ser Met Val Leu Thr Lys Met Lys 115 120 125 Glu Ile Ala Glu Ala Tyr Leu Gly Tyr Pro Val Thr Asn Ala Val Ile 130 135 140 Thr Val Pro Ala Tyr Phe Asn Asp Ser Gln Arg Gln Ala Thr Lys Asp 145 150 155 160 Ala Gly Val Ile Ala Gly Leu Asn Val Leu Arg Ile Ile Asn Glu Pro 165 170 175 Thr Ala Ala Ala Ile Ala Tyr Gly Leu Asp Arg Thr Gly Lys Gly Glu 180 185 190 Arg Asn Val Leu Ile Phe Asp Leu Gly Gly Gly Thr Phe Asp Val Ser 195 200 205 Ile Leu Thr Ile Asp Asp Gly Ile Phe Glu Val Lys Ala Thr Ala Gly 210 215 220 Asp Thr His Leu Gly Gly Glu Asp Phe Asp Asn Arg Leu Val Asn His 225 230 235 240 Phe Val Glu Glu Phe Lys Arg Lys His Lys Lys Asp Ile Ser Gln Asn 245 250 255 Lys Arg Ala Val Arg Arg Leu Arg Thr Ala Cys Glu Arg Ala Lys Arg 260 265 270 Thr Leu Ser Ser Ser Thr Gln Ala Ser Leu Glu Ile Asp Ser Leu Phe 275 280 285 Glu Gly Ile Asp Phe Tyr Thr Ser Ile Thr Arg Ala Arg Phe Glu Glu 290 295 300 Leu Cys Ser Asp Leu Phe Arg Ser Thr Leu Glu Pro Val Glu Lys Ala 305 310 315 320 Leu Arg Asp Ala Lys Leu Asp Lys Ala Gln Ile His Asp Leu Val Leu 325 330 335 Val Gly Gly Ser Thr Arg Ile Pro Lys Val Gln Lys Leu Leu Gln Asp 340 345 350 Phe Phe Asn Gly Arg Asp Leu Asn Lys Ser Ile Asn Pro Asp Glu Ala 355 360 365 Val Ala Tyr Gly Ala Ala Val Gln Ala Ala Ile Leu Met Gly Asp Lys 370 375 380 Ser Glu Asn Val Gln Asp Leu Leu Leu Leu Asp Val Ala Pro Leu Ser 385 390 395 400 Leu Gly Leu Glu Thr Ala Gly Gly Val Met Thr Ala Leu Ile Lys Arg 405 410 415 Asn Ser Thr Ile Pro Thr Lys Gln Thr Gln Ile Phe Thr Thr Tyr Ser 420 425 430 Asp Asn Gln Pro Gly Val Leu Ile Gln Val Tyr Glu Gly Glu Arg Ala 435 440 445 Met Thr Lys Asp Asn Asn Leu Leu Gly Arg Phe Glu Leu Ser Gly Ile 450 455 460 Pro Pro Ala Pro Arg Gly Val Pro Gln Ile Glu Val Thr Phe Asp Ile 465 470 475 480 Asp Ala Asn Gly Ile Leu Asn Val Thr Ala Thr Asp Lys Ser Thr Gly 485 490 495 Lys Ala Asn Lys Ile Thr Ile Thr Asn Asp Lys Gly Arg Leu Ser Lys 500 505 510 Glu Glu Ile Glu Arg Met Val Gln Glu Ala Glu Lys Tyr Lys Ala Glu 515 520 525 Asp Glu Val Gln Arg Glu Arg Val Ser Ala Lys Asn Ala Leu Glu Ser 530 535 540 Tyr Ala Phe Asn Met Lys Ser Ala Val Glu Asp Glu Gly Leu Lys Gly 545 550 555 560 Lys Ile Ser Glu Ala Asp Lys Lys Lys Val Leu Asp Lys Cys Gln Glu 565 570 575 Val Ile Ser Trp Leu Asp Ala Asn Thr Leu Ala Glu Lys Asp Glu Phe 580 585 590 Glu His Lys Arg Lys Glu Leu Glu Gln Val Cys Asn Pro Ile Ile Ser 595 600 605 Gly Leu Tyr Gln Gly Ala Gly Gly Pro Gly Pro Gly Gly Phe Gly Ala 610 615 620 Gln Gly Pro Lys Gly Gly Ser Gly Ser Gly Pro Thr Ile Glu Glu Val 625 630 635 640 Asp 12323PRTHomo sapiens 12Met Asp Ser Lys Tyr Gln Cys Val Lys Leu Asn Asp Gly His Phe Met 1 5 10 15 Pro Val Leu Gly Phe Gly Thr Tyr Ala Pro Ala Glu Val Pro Lys Ser 20 25 30 Lys Ala Leu Glu Ala Val Lys Leu Ala Ile Glu Ala Gly Phe His His 35 40 45 Ile Asp Ser Ala His Val Tyr Asn Asn Glu Glu Gln Val Gly Leu Ala 50 55 60 Ile Arg Ser Lys Ile Ala Asp Gly Ser Val Lys Arg Glu Asp Ile Phe 65 70 75 80 Tyr Thr Ser Lys Leu Trp Ser Asn Ser His Arg Pro Glu Leu Val Arg 85 90 95 Pro Ala Leu Glu Arg Ser Leu Lys Asn Leu Gln Leu Asp Tyr Val Asp 100 105 110 Leu Tyr Leu Ile His Phe Pro Val Ser Val Lys Pro Gly Glu Glu Val 115 120 125 Ile Pro Lys Asp Glu Asn Gly Lys Ile Leu Phe Asp Thr Val Asp Leu 130 135 140 Cys Ala Thr Trp Glu Ala Met Glu Lys Cys Lys Asp Ala Gly Leu Ala 145 150 155 160 Lys Ser Ile Gly Val Ser Asn Phe Asn His Arg Leu Leu Glu Met Ile 165 170 175 Leu Asn Lys Pro Gly Leu Lys Tyr Lys Pro Val Cys Asn Gln Val Glu 180 185 190 Cys His Pro Tyr Phe Asn Gln Arg Lys Leu Leu Asp Phe Cys Lys Ser 195 200 205 Lys Asp Ile Val Leu Val Ala Tyr Ser Ala Leu Gly Ser His Arg Glu 210 215 220 Glu Pro Trp Val Asp Pro Asn Ser Pro Val Leu Leu Glu Asp Pro Val 225 230 235 240 Leu Cys Ala Leu Ala Lys Lys His Lys Arg Thr Pro Ala Leu Ile Ala 245 250 255 Leu Arg Tyr Gln Leu Gln Arg Gly Val Val Val Leu Ala Lys Ser Tyr 260 265 270 Asn Glu Gln Arg Ile Arg Gln Asn Val Gln Val Phe Glu Phe Gln Leu 275 280 285 Thr Ser Glu Glu Met Lys Ala Ile Asp Gly Leu Asn Arg Asn Val Arg 290 295 300 Tyr Leu Thr Leu Asp Ile Phe Ala Gly Pro Pro Asn Tyr Pro Phe Ser 305 310 315 320 Asp Glu Tyr 13215PRTHomo sapiens 13Met Val Phe Arg Arg Phe Val Glu Val Gly Arg Val Ala Tyr Val Ser 1 5 10 15 Phe Gly Pro His Ala Gly Lys Leu Val Ala Ile Val Asp Val Ile Asp 20 25 30 Gln Asn Arg Ala Leu Val Asp Gly Pro Cys Thr Gln Val Arg Arg Gln

35 40 45 Ala Met Pro Phe Lys Cys Met Gln Leu Thr Asp Phe Ile Leu Lys Phe 50 55 60 Pro His Ser Ala His Gln Lys Tyr Val Arg Gln Ala Trp Gln Lys Ala 65 70 75 80 Asp Ile Asn Thr Lys Trp Ala Ala Thr Arg Trp Ala Lys Lys Ile Glu 85 90 95 Ala Arg Glu Arg Lys Ala Lys Met Thr Asp Phe Asp Arg Phe Lys Val 100 105 110 Met Lys Ala Lys Lys Met Arg Asn Arg Ile Ile Lys Asn Glu Val Lys 115 120 125 Lys Leu Gln Lys Ala Ala Leu Leu Lys Ala Ser Pro Lys Lys Ala Pro 130 135 140 Gly Thr Lys Gly Thr Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Lys 145 150 155 160 Val Pro Ala Lys Lys Ile Thr Ala Ala Ser Lys Lys Ala Pro Ala Gln 165 170 175 Lys Val Pro Ala Gln Lys Ala Thr Gly Gln Lys Ala Ala Pro Ala Pro 180 185 190 Lys Ala Gln Lys Gly Gln Lys Ala Pro Ala Gln Lys Ala Pro Ala Pro 195 200 205 Lys Ala Ser Gly Lys Lys Ala 210 215 14822PRTHomo sapiens 14Met Asn Gly His Ile Ser Asn His Pro Ser Ser Phe Gly Met Tyr Pro 1 5 10 15 Ser Gln Met Asn Gly Tyr Gly Ser Ser Pro Thr Phe Ser Gln Thr Asp 20 25 30 Arg Glu His Gly Ser Lys Thr Ser Ala Lys Ala Leu Tyr Glu Gln Arg 35 40 45 Lys Asn Tyr Ala Arg Asp Ser Val Ser Ser Val Ser Asp Ile Ser Gln 50 55 60 Tyr Arg Val Glu His Leu Thr Thr Phe Val Leu Asp Arg Lys Asp Ala 65 70 75 80 Met Ile Thr Val Asp Asp Gly Ile Arg Lys Leu Lys Leu Leu Asp Ala 85 90 95 Lys Gly Lys Val Trp Thr Gln Asp Met Ile Leu Gln Val Asp Asp Arg 100 105 110 Ala Val Ser Leu Ile Asp Leu Glu Ser Lys Asn Glu Leu Glu Asn Phe 115 120 125 Pro Leu Asn Thr Ile Gln His Cys Gln Ala Val Met His Ser Cys Ser 130 135 140 Tyr Asp Ser Val Leu Ala Leu Val Cys Lys Glu Pro Thr Gln Asn Lys 145 150 155 160 Pro Asp Leu His Leu Phe Gln Cys Asp Glu Val Lys Ala Asn Leu Ile 165 170 175 Ser Glu Asp Ile Glu Ser Ala Ile Ser Asp Ser Lys Gly Gly Lys Gln 180 185 190 Lys Arg Arg Pro Asp Ala Leu Arg Met Ile Ser Asn Ala Asp Pro Ser 195 200 205 Ile Pro Pro Pro Pro Arg Ala Pro Ala Pro Ala Pro Pro Gly Thr Val 210 215 220 Thr Gln Val Asp Val Arg Ser Arg Val Ala Ala Trp Ser Ala Trp Ala 225 230 235 240 Ala Asp Gln Gly Asp Phe Glu Lys Pro Arg Gln Tyr His Glu Gln Glu 245 250 255 Glu Thr Pro Glu Met Met Ala Ala Arg Ile Asp Arg Asp Val Gln Ile 260 265 270 Leu Asn His Ile Leu Asp Asp Ile Glu Phe Phe Ile Thr Lys Leu Gln 275 280 285 Lys Ala Ala Glu Ala Phe Ser Glu Leu Ser Lys Arg Lys Lys Asn Lys 290 295 300 Lys Gly Lys Arg Lys Gly Pro Gly Glu Gly Val Leu Thr Leu Arg Ala 305 310 315 320 Lys Pro Pro Pro Pro Asp Glu Phe Leu Asp Cys Phe Gln Lys Phe Lys 325 330 335 His Gly Phe Asn Leu Leu Ala Lys Leu Lys Ser His Ile Gln Asn Pro 340 345 350 Ser Ala Ala Asp Leu Val His Phe Leu Phe Thr Pro Leu Asn Met Val 355 360 365 Val Gln Ala Thr Gly Gly Pro Glu Leu Ala Ser Ser Val Leu Ser Pro 370 375 380 Leu Leu Asn Lys Asp Thr Ile Asp Phe Leu Asn Tyr Thr Val Asn Gly 385 390 395 400 Asp Glu Arg Gln Leu Trp Met Ser Leu Gly Gly Thr Trp Met Lys Ala 405 410 415 Arg Ala Glu Trp Pro Lys Glu Gln Phe Ile Pro Pro Tyr Val Pro Arg 420 425 430 Phe Arg Asn Gly Trp Glu Pro Pro Met Leu Asn Phe Met Gly Ala Thr 435 440 445 Met Glu Gln Asp Leu Tyr Gln Leu Ala Glu Ser Val Ala Asn Val Ala 450 455 460 Glu His Gln Arg Lys Gln Glu Ile Lys Arg Leu Ser Thr Glu His Ser 465 470 475 480 Ser Val Ser Glu Tyr His Pro Ala Asp Gly Tyr Ala Phe Ser Ser Asn 485 490 495 Ile Tyr Thr Arg Gly Ser His Leu Asp Gln Gly Glu Ala Ala Val Ala 500 505 510 Phe Lys Pro Thr Ser Asn Arg His Ile Asp Arg Asn Tyr Glu Pro Leu 515 520 525 Lys Thr Gln Pro Lys Lys Tyr Ala Lys Ser Lys Tyr Asp Phe Val Ala 530 535 540 Arg Asn Asn Ser Glu Leu Ser Val Leu Lys Asp Asp Ile Leu Glu Ile 545 550 555 560 Leu Asp Asp Arg Lys Gln Trp Trp Lys Val Arg Asn Ala Ser Gly Asp 565 570 575 Ser Gly Phe Val Pro Asn Asn Ile Leu Asp Ile Val Arg Pro Pro Glu 580 585 590 Ser Gly Leu Gly Arg Ala Asp Pro Pro Tyr Thr His Thr Ile Gln Lys 595 600 605 Gln Arg Met Glu Tyr Gly Pro Arg Pro Ala Asp Thr Pro Pro Ala Pro 610 615 620 Ser Pro Pro Pro Thr Pro Ala Pro Val Pro Val Pro Leu Pro Pro Ser 625 630 635 640 Thr Pro Ala Pro Val Pro Val Ser Lys Val Pro Ala Asn Ile Thr Arg 645 650 655 Gln Asn Ser Ser Ser Ser Asp Ser Gly Gly Ser Ile Val Arg Asp Ser 660 665 670 Gln Arg His Lys Gln Leu Pro Val Asp Arg Arg Lys Ser Gln Met Glu 675 680 685 Glu Val Gln Asp Glu Leu Ile His Arg Leu Thr Ile Gly Arg Ser Ala 690 695 700 Ala Gln Lys Lys Phe His Val Pro Arg Gln Asn Val Pro Val Ile Asn 705 710 715 720 Ile Thr Tyr Asp Ser Thr Pro Glu Asp Val Lys Thr Trp Leu Gln Ser 725 730 735 Lys Gly Phe Asn Pro Val Thr Val Asn Ser Leu Gly Val Leu Asn Gly 740 745 750 Ala Gln Leu Phe Ser Leu Asn Lys Asp Glu Leu Arg Thr Val Cys Pro 755 760 765 Glu Gly Ala Arg Val Tyr Ser Gln Ile Thr Val Gln Lys Ala Ala Leu 770 775 780 Glu Asp Ser Ser Gly Ser Ser Glu Leu Gln Glu Ile Met Arg Arg Arg 785 790 795 800 Gln Glu Lys Ile Ser Ala Ala Ala Ser Asp Ser Gly Val Glu Ser Phe 805 810 815 Asp Glu Gly Ser Ser His 820 15415PRTHomo sapiens 15Met Glu Asp Leu Cys Val Ala Asn Thr Leu Phe Ala Leu Asn Leu Phe 1 5 10 15 Lys His Leu Ala Lys Ala Ser Pro Thr Gln Asn Leu Phe Leu Ser Pro 20 25 30 Trp Ser Ile Ser Ser Thr Met Ala Met Val Tyr Met Gly Ser Arg Gly 35 40 45 Ser Thr Glu Asp Gln Met Ala Lys Val Leu Gln Phe Asn Glu Val Gly 50 55 60 Ala Asn Ala Val Thr Pro Met Thr Pro Glu Asn Phe Thr Ser Cys Gly 65 70 75 80 Phe Met Gln Gln Ile Gln Lys Gly Ser Tyr Pro Asp Ala Ile Leu Gln 85 90 95 Ala Gln Ala Ala Asp Lys Ile His Ser Ser Phe Arg Ser Leu Ser Ser 100 105 110 Ala Ile Asn Ala Ser Thr Gly Asn Tyr Leu Leu Glu Ser Val Asn Lys 115 120 125 Leu Phe Gly Glu Lys Ser Ala Ser Phe Arg Glu Glu Tyr Ile Arg Leu 130 135 140 Cys Gln Lys Tyr Tyr Ser Ser Glu Pro Gln Ala Val Asp Phe Leu Glu 145 150 155 160 Cys Ala Glu Glu Ala Arg Lys Lys Ile Asn Ser Trp Val Lys Thr Gln 165 170 175 Thr Lys Gly Lys Ile Pro Asn Leu Leu Pro Glu Gly Ser Val Asp Gly 180 185 190 Asp Thr Arg Met Val Leu Val Asn Ala Val Tyr Phe Lys Gly Lys Trp 195 200 205 Lys Thr Pro Phe Glu Lys Lys Leu Asn Gly Leu Tyr Pro Phe Arg Val 210 215 220 Asn Ser Ala Gln Arg Thr Pro Val Gln Met Met Tyr Leu Arg Glu Lys 225 230 235 240 Leu Asn Ile Gly Tyr Ile Glu Asp Leu Lys Ala Gln Ile Leu Glu Leu 245 250 255 Pro Tyr Ala Gly Asp Val Ser Met Phe Leu Leu Leu Pro Asp Glu Ile 260 265 270 Ala Asp Val Ser Thr Gly Leu Glu Leu Leu Glu Ser Glu Ile Thr Tyr 275 280 285 Asp Lys Leu Asn Lys Trp Thr Ser Lys Asp Lys Met Ala Glu Asp Glu 290 295 300 Val Glu Val Tyr Ile Pro Gln Phe Lys Leu Glu Glu His Tyr Glu Leu 305 310 315 320 Arg Ser Ile Leu Arg Ser Met Gly Met Glu Asp Ala Phe Asn Lys Gly 325 330 335 Arg Ala Asn Phe Ser Gly Met Ser Glu Arg Asn Asp Leu Phe Leu Ser 340 345 350 Glu Val Phe His Gln Ala Met Val Asp Val Asn Glu Glu Gly Thr Glu 355 360 365 Ala Ala Ala Gly Thr Gly Gly Val Met Thr Gly Arg Thr Gly His Gly 370 375 380 Gly Pro Gln Phe Val Ala Asp His Pro Phe Leu Phe Leu Ile Met His 385 390 395 400 Lys Ile Thr Asn Cys Ile Leu Phe Phe Gly Arg Phe Ser Ser Pro 405 410 415 16283PRTHomo sapiens 16Met Cys Asn Thr Pro Thr Tyr Cys Asp Leu Gly Lys Ala Ala Lys Asp 1 5 10 15 Val Phe Asn Lys Gly Tyr Gly Phe Gly Met Val Lys Ile Asp Leu Lys 20 25 30 Thr Lys Ser Cys Ser Gly Val Glu Phe Ser Thr Ser Gly His Ala Tyr 35 40 45 Thr Asp Thr Gly Lys Ala Ser Gly Asn Leu Glu Thr Lys Tyr Lys Val 50 55 60 Cys Asn Tyr Gly Leu Thr Phe Thr Gln Lys Trp Asn Thr Asp Asn Thr 65 70 75 80 Leu Gly Thr Glu Ile Ser Trp Glu Asn Lys Leu Ala Glu Gly Leu Lys 85 90 95 Leu Thr Leu Asp Thr Ile Phe Val Pro Asn Thr Gly Lys Lys Ser Gly 100 105 110 Lys Leu Lys Ala Ser Tyr Lys Arg Asp Cys Phe Ser Val Gly Ser Asn 115 120 125 Val Asp Ile Asp Phe Ser Gly Pro Thr Ile Tyr Gly Trp Ala Val Leu 130 135 140 Ala Phe Glu Gly Trp Leu Ala Gly Tyr Gln Met Ser Phe Asp Thr Ala 145 150 155 160 Lys Ser Lys Leu Ser Gln Asn Asn Phe Ala Leu Gly Tyr Lys Ala Ala 165 170 175 Asp Phe Gln Leu His Thr His Val Asn Asp Gly Thr Glu Phe Gly Gly 180 185 190 Ser Ile Tyr Gln Lys Val Asn Glu Lys Ile Glu Thr Ser Ile Asn Leu 195 200 205 Ala Trp Thr Ala Gly Ser Asn Asn Thr Arg Phe Gly Ile Ala Ala Lys 210 215 220 Tyr Met Leu Asp Cys Arg Thr Ser Leu Ser Ala Lys Val Asn Asn Ala 225 230 235 240 Ser Leu Ile Gly Leu Gly Tyr Thr Gln Thr Leu Arg Pro Gly Val Lys 245 250 255 Leu Thr Leu Ser Ala Leu Ile Asp Gly Lys Asn Phe Ser Ala Gly Gly 260 265 270 His Lys Val Gly Leu Gly Phe Glu Leu Glu Ala 275 280 17346PRTHomo sapiens 17Met Ala Met Val Ser Glu Phe Leu Lys Gln Ala Trp Phe Ile Glu Asn 1 5 10 15 Glu Glu Gln Glu Tyr Val Gln Thr Val Lys Ser Ser Lys Gly Gly Pro 20 25 30 Gly Ser Ala Val Ser Pro Tyr Pro Thr Phe Asn Pro Ser Ser Asp Val 35 40 45 Ala Ala Leu His Lys Ala Ile Met Val Lys Gly Val Asp Glu Ala Thr 50 55 60 Ile Ile Asp Ile Leu Thr Lys Arg Asn Asn Ala Gln Arg Gln Gln Ile 65 70 75 80 Lys Ala Ala Tyr Leu Gln Glu Thr Gly Lys Pro Leu Asp Glu Thr Leu 85 90 95 Lys Lys Ala Leu Thr Gly His Leu Glu Glu Val Val Leu Ala Leu Leu 100 105 110 Lys Thr Pro Ala Gln Phe Asp Ala Asp Glu Leu Arg Ala Ala Met Lys 115 120 125 Gly Leu Gly Thr Asp Glu Asp Thr Leu Ile Glu Ile Leu Ala Ser Arg 130 135 140 Thr Asn Lys Glu Ile Arg Asp Ile Asn Arg Val Tyr Arg Glu Glu Leu 145 150 155 160 Lys Arg Asp Leu Ala Lys Asp Ile Thr Ser Asp Thr Ser Gly Asp Phe 165 170 175 Arg Asn Ala Leu Leu Ser Leu Ala Lys Gly Asp Arg Ser Glu Asp Phe 180 185 190 Gly Val Asn Glu Asp Leu Ala Asp Ser Asp Ala Arg Ala Leu Tyr Glu 195 200 205 Ala Gly Glu Arg Arg Lys Gly Thr Asp Val Asn Val Phe Asn Thr Ile 210 215 220 Leu Thr Thr Arg Ser Tyr Pro Gln Leu Arg Arg Val Phe Gln Lys Tyr 225 230 235 240 Thr Lys Tyr Ser Lys His Asp Met Asn Lys Val Leu Asp Leu Glu Leu 245 250 255 Lys Gly Asp Ile Glu Lys Cys Leu Thr Ala Ile Val Lys Cys Ala Thr 260 265 270 Ser Lys Pro Ala Phe Phe Ala Glu Lys Leu His Gln Ala Met Lys Gly 275 280 285 Val Gly Thr Arg His Lys Ala Leu Ile Arg Ile Met Val Ser Arg Ser 290 295 300 Glu Ile Asp Met Asn Asp Ile Lys Ala Phe Tyr Gln Lys Met Tyr Gly 305 310 315 320 Ile Ser Leu Cys Gln Ala Ile Leu Asp Glu Thr Lys Gly Asp Tyr Glu 325 330 335 Lys Ile Leu Val Ala Leu Cys Gly Gly Asn 340 345 1898PRTHomo sapiens 18Met Met Cys Gly Ala Pro Ser Ala Thr Gln Pro Ala Thr Ala Glu Thr 1 5 10 15 Gln His Ile Ala Asp Gln Val Arg Ser Gln Leu Glu Glu Lys Glu Asn 20 25 30 Lys Lys Phe Pro Val Phe Lys Ala Val Ser Phe Lys Ser Gln Val Val 35 40 45 Ala Gly Thr Asn Tyr Phe Ile Lys Val His Val Gly Asp Glu Asp Phe 50 55 60 Val His Leu Arg Val Phe Gln Ser Leu Pro His Glu Asn Lys Pro Leu 65 70 75 80 Thr Leu Ser Asn Tyr Gln Thr Asn Lys Ala Lys His Asp Glu Leu Thr 85 90 95 Tyr Phe 191675PRTHomo sapiens 19Met Ala Gln Ile Leu Pro Ile Arg Phe Gln Glu His Leu Gln Leu Gln 1 5 10 15 Asn Leu Gly Ile Asn Pro Ala Asn Ile Gly Phe Ser Thr Leu Thr Met 20 25 30 Glu Ser Asp Lys Phe Ile Cys Ile Arg Glu Lys Val Gly Glu Gln Ala 35 40 45 Gln Val Val Ile Ile Asp Met Asn Asp Pro Ser Asn Pro Ile Arg Arg 50 55 60 Pro Ile Ser Ala Asp Ser Ala Ile Met Asn Pro Ala Ser Lys Val Ile 65 70 75 80 Ala Leu Lys Ala Gly Lys Thr Leu Gln Ile Phe Asn Ile Glu Met Lys 85 90 95 Ser Lys Met Lys Ala His Thr Met Thr Asp Asp Val Thr Phe Trp Lys 100 105 110 Trp Ile Ser Leu Asn Thr Val Ala Leu Val Thr Asp Asn Ala Val Tyr 115 120 125 His Trp Ser Met Glu Gly Glu Ser Gln Pro Val Lys Met Phe Asp Arg 130 135 140 His Ser Ser Leu Ala Gly Cys Gln Ile Ile Asn Tyr Arg

Thr Asp Ala 145 150 155 160 Lys Gln Lys Trp Leu Leu Leu Thr Gly Ile Ser Ala Gln Gln Asn Arg 165 170 175 Val Val Gly Ala Met Gln Leu Tyr Ser Val Asp Arg Lys Val Ser Gln 180 185 190 Pro Ile Glu Gly His Ala Ala Ser Phe Ala Gln Phe Lys Met Glu Gly 195 200 205 Asn Ala Glu Glu Ser Thr Leu Phe Cys Phe Ala Val Arg Gly Gln Ala 210 215 220 Gly Gly Lys Leu His Ile Ile Glu Val Gly Thr Pro Pro Thr Gly Asn 225 230 235 240 Gln Pro Phe Pro Lys Lys Ala Val Asp Val Phe Phe Pro Pro Glu Ala 245 250 255 Gln Asn Asp Phe Pro Val Ala Met Gln Ile Ser Glu Lys His Asp Val 260 265 270 Val Phe Leu Ile Thr Lys Tyr Gly Tyr Ile His Leu Tyr Asp Leu Glu 275 280 285 Thr Gly Thr Cys Ile Tyr Met Asn Arg Ile Ser Gly Glu Thr Ile Phe 290 295 300 Val Thr Ala Pro His Glu Ala Thr Ala Gly Ile Ile Gly Val Asn Arg 305 310 315 320 Lys Gly Gln Val Leu Ser Val Cys Val Glu Glu Glu Asn Ile Ile Pro 325 330 335 Tyr Ile Thr Asn Val Leu Gln Asn Pro Asp Leu Ala Leu Arg Met Ala 340 345 350 Val Arg Asn Asn Leu Ala Gly Ala Glu Glu Leu Phe Ala Arg Lys Phe 355 360 365 Asn Ala Leu Phe Ala Gln Gly Asn Tyr Ser Glu Ala Ala Lys Val Ala 370 375 380 Ala Asn Ala Pro Lys Gly Ile Leu Arg Thr Pro Asp Thr Ile Arg Arg 385 390 395 400 Phe Gln Ser Val Pro Ala Gln Pro Gly Gln Thr Ser Pro Leu Leu Gln 405 410 415 Tyr Phe Gly Ile Leu Leu Asp Gln Gly Gln Leu Asn Lys Tyr Glu Ser 420 425 430 Leu Glu Leu Cys Arg Pro Val Leu Gln Gln Gly Arg Lys Gln Leu Leu 435 440 445 Glu Lys Trp Leu Lys Glu Asp Lys Leu Glu Cys Ser Glu Glu Leu Gly 450 455 460 Asp Leu Val Lys Ser Val Asp Pro Thr Leu Ala Leu Ser Val Tyr Leu 465 470 475 480 Arg Ala Asn Val Pro Asn Lys Val Ile Gln Cys Phe Ala Glu Thr Gly 485 490 495 Gln Val Gln Lys Ile Val Leu Tyr Ala Lys Lys Val Gly Tyr Thr Pro 500 505 510 Asp Trp Ile Phe Leu Leu Arg Asn Val Met Arg Ile Ser Pro Asp Gln 515 520 525 Gly Gln Gln Phe Ala Gln Met Leu Val Gln Asp Glu Glu Pro Leu Ala 530 535 540 Asp Ile Thr Gln Ile Val Asp Val Phe Met Glu Tyr Asn Leu Ile Gln 545 550 555 560 Gln Cys Thr Ala Phe Leu Leu Asp Ala Leu Lys Asn Asn Arg Pro Ser 565 570 575 Glu Gly Pro Leu Gln Thr Arg Leu Leu Glu Met Asn Leu Met His Ala 580 585 590 Pro Gln Val Ala Asp Ala Ile Leu Gly Asn Gln Met Phe Thr His Tyr 595 600 605 Asp Arg Ala His Ile Ala Gln Leu Cys Glu Lys Ala Gly Leu Leu Gln 610 615 620 Arg Ala Leu Glu His Phe Thr Asp Leu Tyr Asp Ile Lys Arg Ala Val 625 630 635 640 Val His Thr His Leu Leu Asn Pro Glu Trp Leu Val Asn Tyr Phe Gly 645 650 655 Ser Leu Ser Val Glu Asp Ser Leu Glu Cys Leu Arg Ala Met Leu Ser 660 665 670 Ala Asn Ile Arg Gln Asn Leu Gln Ile Cys Val Gln Val Ala Ser Lys 675 680 685 Tyr His Glu Gln Leu Ser Thr Gln Ser Leu Ile Glu Leu Phe Glu Ser 690 695 700 Phe Lys Ser Phe Glu Gly Leu Phe Tyr Phe Leu Gly Ser Ile Val Asn 705 710 715 720 Phe Ser Gln Asp Pro Asp Val His Phe Lys Tyr Ile Gln Ala Ala Cys 725 730 735 Lys Thr Gly Gln Ile Lys Glu Val Glu Arg Ile Cys Arg Glu Ser Asn 740 745 750 Cys Tyr Asp Pro Glu Arg Val Lys Asn Phe Leu Lys Glu Ala Lys Leu 755 760 765 Thr Asp Gln Leu Pro Leu Ile Ile Val Cys Asp Arg Phe Asp Phe Val 770 775 780 His Asp Leu Val Leu Tyr Leu Tyr Arg Asn Asn Leu Gln Lys Tyr Ile 785 790 795 800 Glu Ile Tyr Val Gln Lys Val Asn Pro Ser Arg Leu Pro Val Val Ile 805 810 815 Gly Gly Leu Leu Asp Val Asp Cys Ser Glu Asp Val Ile Lys Asn Leu 820 825 830 Ile Leu Val Val Arg Gly Gln Phe Ser Thr Asp Glu Leu Val Ala Glu 835 840 845 Val Glu Lys Arg Asn Arg Leu Lys Leu Leu Leu Pro Trp Leu Glu Ala 850 855 860 Arg Ile His Glu Gly Cys Glu Glu Pro Ala Thr His Asn Ala Leu Ala 865 870 875 880 Lys Ile Tyr Ile Asp Ser Asn Asn Asn Pro Glu Arg Phe Leu Arg Glu 885 890 895 Asn Pro Tyr Tyr Asp Ser Arg Val Val Gly Lys Tyr Cys Glu Lys Arg 900 905 910 Asp Pro His Leu Ala Cys Val Ala Tyr Glu Arg Gly Gln Cys Asp Leu 915 920 925 Glu Leu Ile Asn Val Cys Asn Glu Asn Ser Leu Phe Lys Ser Leu Ser 930 935 940 Arg Tyr Leu Val Arg Arg Lys Asp Pro Glu Leu Trp Gly Ser Val Leu 945 950 955 960 Leu Glu Ser Asn Pro Tyr Arg Arg Pro Leu Ile Asp Gln Val Val Gln 965 970 975 Thr Ala Leu Ser Glu Thr Gln Asp Pro Glu Glu Val Ser Val Thr Val 980 985 990 Lys Ala Phe Met Thr Ala Asp Leu Pro Asn Glu Leu Ile Glu Leu Leu 995 1000 1005 Glu Lys Ile Val Leu Asp Asn Ser Val Phe Ser Glu His Arg Asn 1010 1015 1020 Leu Gln Asn Leu Leu Ile Leu Thr Ala Ile Lys Ala Asp Arg Thr 1025 1030 1035 Arg Val Met Glu Tyr Ile Asn Arg Leu Asp Asn Tyr Asp Ala Pro 1040 1045 1050 Asp Ile Ala Asn Ile Ala Ile Ser Asn Glu Leu Phe Glu Glu Ala 1055 1060 1065 Phe Ala Ile Phe Arg Lys Phe Asp Val Asn Thr Ser Ala Val Gln 1070 1075 1080 Val Leu Ile Glu His Ile Gly Asn Leu Asp Arg Ala Tyr Glu Phe 1085 1090 1095 Ala Glu Arg Cys Asn Glu Pro Ala Val Trp Ser Gln Leu Ala Lys 1100 1105 1110 Ala Gln Leu Gln Lys Gly Met Val Lys Glu Ala Ile Asp Ser Tyr 1115 1120 1125 Ile Lys Ala Asp Asp Pro Ser Ser Tyr Met Glu Val Val Gln Ala 1130 1135 1140 Ala Asn Thr Ser Gly Asn Trp Glu Glu Leu Val Lys Tyr Leu Gln 1145 1150 1155 Met Ala Arg Lys Lys Ala Arg Glu Ser Tyr Val Glu Thr Glu Leu 1160 1165 1170 Ile Phe Ala Leu Ala Lys Thr Asn Arg Leu Ala Glu Leu Glu Glu 1175 1180 1185 Phe Ile Asn Gly Pro Asn Asn Ala His Ile Gln Gln Val Gly Asp 1190 1195 1200 Arg Cys Tyr Asp Glu Lys Met Tyr Asp Ala Ala Lys Leu Leu Tyr 1205 1210 1215 Asn Asn Val Ser Asn Phe Gly Arg Leu Ala Ser Thr Leu Val His 1220 1225 1230 Leu Gly Glu Tyr Gln Ala Ala Val Asp Gly Ala Arg Lys Ala Asn 1235 1240 1245 Ser Thr Arg Thr Trp Lys Glu Val Cys Phe Ala Cys Val Asp Gly 1250 1255 1260 Lys Glu Phe Arg Leu Ala Gln Met Cys Gly Leu His Ile Val Val 1265 1270 1275 His Ala Asp Glu Leu Glu Glu Leu Ile Asn Tyr Tyr Gln Asp Arg 1280 1285 1290 Gly Tyr Phe Glu Glu Leu Ile Thr Met Leu Glu Ala Ala Leu Gly 1295 1300 1305 Leu Glu Arg Ala His Met Gly Met Phe Thr Glu Leu Ala Ile Leu 1310 1315 1320 Tyr Ser Lys Phe Lys Pro Gln Lys Met Arg Glu His Leu Glu Leu 1325 1330 1335 Phe Trp Ser Arg Val Asn Ile Pro Lys Val Leu Arg Ala Ala Glu 1340 1345 1350 Gln Ala His Leu Trp Ala Glu Leu Val Phe Leu Tyr Asp Lys Tyr 1355 1360 1365 Glu Glu Tyr Asp Asn Ala Ile Ile Thr Met Met Asn His Pro Thr 1370 1375 1380 Asp Ala Trp Lys Glu Gly Gln Phe Lys Asp Ile Ile Thr Lys Val 1385 1390 1395 Ala Asn Val Glu Leu Tyr Tyr Arg Ala Ile Gln Phe Tyr Leu Glu 1400 1405 1410 Phe Lys Pro Leu Leu Leu Asn Asp Leu Leu Met Val Leu Ser Pro 1415 1420 1425 Arg Leu Asp His Thr Arg Ala Val Asn Tyr Phe Ser Lys Val Lys 1430 1435 1440 Gln Leu Pro Leu Val Lys Pro Tyr Leu Arg Ser Val Gln Asn His 1445 1450 1455 Asn Asn Lys Ser Val Asn Glu Ser Leu Asn Asn Leu Phe Ile Thr 1460 1465 1470 Glu Glu Asp Tyr Gln Ala Leu Arg Thr Ser Ile Asp Ala Tyr Asp 1475 1480 1485 Asn Phe Asp Asn Ile Ser Leu Ala Gln Arg Leu Glu Lys His Glu 1490 1495 1500 Leu Ile Glu Phe Arg Arg Ile Ala Ala Tyr Leu Phe Lys Gly Asn 1505 1510 1515 Asn Arg Trp Lys Gln Ser Val Glu Leu Cys Lys Lys Asp Ser Leu 1520 1525 1530 Tyr Lys Asp Ala Met Gln Tyr Ala Ser Glu Ser Lys Asp Thr Glu 1535 1540 1545 Leu Ala Glu Glu Leu Leu Gln Trp Phe Leu Gln Glu Glu Lys Arg 1550 1555 1560 Glu Cys Phe Gly Ala Cys Leu Phe Thr Cys Tyr Asp Leu Leu Arg 1565 1570 1575 Pro Asp Val Val Leu Glu Thr Ala Trp Arg His Asn Ile Met Asp 1580 1585 1590 Phe Ala Met Pro Tyr Phe Ile Gln Val Met Lys Glu Tyr Leu Thr 1595 1600 1605 Lys Val Asp Lys Leu Asp Ala Ser Glu Ser Leu Arg Lys Glu Glu 1610 1615 1620 Glu Gln Ala Thr Glu Thr Gln Pro Ile Val Tyr Gly Gln Pro Gln 1625 1630 1635 Leu Met Leu Thr Ala Gly Pro Ser Val Ala Val Pro Pro Gln Ala 1640 1645 1650 Pro Phe Gly Tyr Gly Tyr Thr Ala Pro Pro Tyr Gly Gln Pro Gln 1655 1660 1665 Pro Gly Phe Gly Tyr Ser Met 1670 1675 20462PRTHomo sapiens 20Met Gly Lys Glu Lys Thr His Ile Asn Ile Val Val Ile Gly His Val 1 5 10 15 Asp Ser Gly Lys Ser Thr Thr Thr Gly His Leu Ile Tyr Lys Cys Gly 20 25 30 Gly Ile Asp Lys Arg Thr Ile Glu Lys Phe Glu Lys Glu Ala Ala Glu 35 40 45 Met Gly Lys Gly Ser Phe Lys Tyr Ala Trp Val Leu Asp Lys Leu Lys 50 55 60 Ala Glu Arg Glu Arg Gly Ile Thr Ile Asp Ile Ser Leu Trp Lys Phe 65 70 75 80 Glu Thr Ser Lys Tyr Tyr Val Thr Ile Ile Asp Ala Pro Gly His Arg 85 90 95 Asp Phe Ile Lys Asn Met Ile Thr Gly Thr Ser Gln Ala Asp Cys Ala 100 105 110 Val Leu Ile Val Ala Ala Gly Val Gly Glu Phe Glu Ala Gly Ile Ser 115 120 125 Lys Asn Gly Gln Thr Arg Glu His Ala Leu Leu Ala Tyr Thr Leu Gly 130 135 140 Val Lys Gln Leu Ile Val Gly Val Asn Lys Met Asp Ser Thr Glu Pro 145 150 155 160 Pro Tyr Ser Gln Lys Arg Tyr Glu Glu Ile Val Lys Glu Val Ser Thr 165 170 175 Tyr Ile Lys Lys Ile Gly Tyr Asn Pro Asp Thr Val Ala Phe Val Pro 180 185 190 Ile Ser Gly Trp Asn Gly Asp Asn Met Leu Glu Pro Ser Ala Asn Met 195 200 205 Pro Trp Phe Lys Gly Trp Lys Val Thr Arg Lys Asp Gly Asn Ala Ser 210 215 220 Gly Thr Thr Leu Leu Glu Ala Leu Asp Cys Ile Leu Pro Pro Thr Arg 225 230 235 240 Pro Thr Asp Lys Pro Leu Arg Leu Pro Leu Gln Asp Val Tyr Lys Ile 245 250 255 Gly Gly Ile Gly Thr Val Pro Val Gly Arg Val Glu Thr Gly Val Leu 260 265 270 Lys Pro Gly Met Val Val Thr Phe Ala Pro Val Asn Val Thr Thr Glu 275 280 285 Val Lys Ser Val Glu Met His His Glu Ala Leu Ser Glu Ala Leu Pro 290 295 300 Gly Asp Asn Val Gly Phe Asn Val Lys Asn Val Ser Val Lys Asp Val 305 310 315 320 Arg Arg Gly Asn Val Ala Gly Asp Ser Lys Asn Asp Pro Pro Met Glu 325 330 335 Ala Ala Gly Phe Thr Ala Gln Val Ile Ile Leu Asn His Pro Gly Gln 340 345 350 Ile Ser Ala Gly Tyr Ala Pro Val Leu Asp Cys His Thr Ala His Ile 355 360 365 Ala Cys Lys Phe Ala Glu Leu Lys Glu Lys Ile Asp Arg Arg Ser Gly 370 375 380 Lys Lys Leu Glu Asp Gly Pro Lys Phe Leu Lys Ser Gly Asp Ala Ala 385 390 395 400 Ile Val Asp Met Val Pro Gly Lys Pro Met Cys Val Glu Ser Phe Ser 405 410 415 Asp Tyr Pro Pro Leu Gly Arg Phe Ala Val Arg Asp Met Arg Gln Thr 420 425 430 Val Ala Val Gly Val Ile Lys Ala Val Asp Lys Lys Ala Ala Gly Ala 435 440 445 Gly Lys Val Thr Lys Ser Ala Gln Lys Ala Gln Lys Ala Lys 450 455 460 21339PRTHomo sapiens 21Met Ser Thr Val His Glu Ile Leu Cys Lys Leu Ser Leu Glu Gly Asp 1 5 10 15 His Ser Thr Pro Pro Ser Ala Tyr Gly Ser Val Lys Ala Tyr Thr Asn 20 25 30 Phe Asp Ala Glu Arg Asp Ala Leu Asn Ile Glu Thr Ala Ile Lys Thr 35 40 45 Lys Gly Val Asp Glu Val Thr Ile Val Asn Ile Leu Thr Asn Arg Ser 50 55 60 Asn Ala Gln Arg Gln Asp Ile Ala Phe Ala Tyr Gln Arg Arg Thr Lys 65 70 75 80 Lys Glu Leu Ala Ser Ala Leu Lys Ser Ala Leu Ser Gly His Leu Glu 85 90 95 Thr Val Ile Leu Gly Leu Leu Lys Thr Pro Ala Gln Tyr Asp Ala Ser 100 105 110 Glu Leu Lys Ala Ser Met Lys Gly Leu Gly Thr Asp Glu Asp Ser Leu 115 120 125 Ile Glu Ile Ile Cys Ser Arg Thr Asn Gln Glu Leu Gln Glu Ile Asn 130 135 140 Arg Val Tyr Lys Glu Met Tyr Lys Thr Asp Leu Glu Lys Asp Ile Ile 145 150 155 160 Ser Asp Thr Ser Gly Asp Phe Arg Lys Leu Met Val Ala Leu Ala Lys 165 170 175 Gly Arg Arg Ala Glu Asp Gly Ser Val Ile Asp Tyr Glu Leu Ile Asp 180 185 190 Gln Asp Ala Arg Asp Leu Tyr Asp Ala Gly Val Lys Arg Lys Gly Thr 195 200 205 Asp Val Pro Lys Trp Ile Ser Ile Met Thr Glu Arg Ser Val Pro His 210 215 220 Leu Gln Lys Val Phe Asp Arg Tyr Lys Ser Tyr Ser Pro Tyr Asp Met 225 230 235 240 Leu Glu Ser Ile Arg Lys Glu Val Lys Gly Asp Leu Glu Asn Ala Phe 245 250 255 Leu Asn Leu Val Gln Cys Ile Gln Asn Lys Pro Leu Tyr Phe Ala Asp 260 265 270 Arg Leu Tyr Asp Ser Met Lys Gly Lys Gly Thr Arg Asp Lys Val

Leu 275 280 285 Ile Arg Ile Met Val Ser Arg Ser Glu Val Asp Met Leu Lys Ile Arg 290 295 300 Ser Glu Phe Lys Arg Lys Tyr Gly Lys Ser Leu Tyr Tyr Tyr Ile Gln 305 310 315 320 Gln Asp Thr Lys Gly Asp Tyr Gln Lys Ala Leu Leu Tyr Leu Cys Gly 325 330 335 Gly Asp Asp 22516PRTHomo sapiens 22Met Ser Pro Glu Ala Gln Pro Gln Arg Thr Lys Gly Pro Gln Gln Pro 1 5 10 15 Cys Arg Ser Pro Ile Val Lys Pro Gly Leu Pro Ser Phe Arg Pro Ser 20 25 30 Ser Cys Thr Gln Pro Trp Leu Thr His Ser Trp Ser Thr Cys Ala Ala 35 40 45 Trp Thr Leu Ile His His Pro Ser Gln Pro Gly Thr Leu Ala Ser Ser 50 55 60 Val Pro Leu Tyr His Ala Glu Thr Ile Lys Asn Val Arg Thr Ala Thr 65 70 75 80 Glu Ser Phe Ala Ser Asp Pro Ile Leu Tyr Arg Pro Val Ala Val Ala 85 90 95 Leu Asp Thr Lys Gly Pro Glu Ile Arg Thr Gly Leu Ile Lys Gly Ser 100 105 110 Gly Thr Ala Glu Val Glu Leu Lys Lys Gly Ala Thr Leu Lys Ile Thr 115 120 125 Leu Asp Asn Ala Tyr Met Glu Lys Cys Asp Glu Asn Ile Leu Trp Leu 130 135 140 Asp Tyr Lys Asn Ile Cys Lys Val Val Glu Val Gly Ser Lys Ile Tyr 145 150 155 160 Val Asp Asp Gly Leu Ile Ser Leu Gln Val Lys Gln Lys Gly Ala Asp 165 170 175 Phe Leu Val Thr Glu Val Glu Asn Gly Gly Ser Leu Gly Ser Lys Lys 180 185 190 Gly Val Asn Leu Pro Gly Ala Ala Val Asp Leu Pro Ala Val Ser Glu 195 200 205 Lys Asp Ile Gln Asp Leu Lys Phe Gly Val Glu Gln Asp Val Asp Met 210 215 220 Val Phe Ala Ser Phe Ile Arg Lys Ala Ser Asp Val His Glu Val Arg 225 230 235 240 Lys Val Leu Gly Glu Lys Gly Lys Asn Ile Lys Ile Ile Ser Lys Ile 245 250 255 Glu Asn His Glu Gly Val Arg Arg Phe Asp Glu Ile Leu Glu Ala Ser 260 265 270 Asp Gly Ile Met Val Ala Arg Gly Asp Leu Gly Ile Glu Ile Pro Ala 275 280 285 Glu Lys Val Phe Leu Ala Gln Lys Met Met Ile Gly Arg Cys Asn Arg 290 295 300 Ala Gly Lys Pro Val Ile Cys Ala Thr Gln Met Leu Glu Ser Met Ile 305 310 315 320 Lys Lys Pro Arg Pro Thr Arg Ala Glu Gly Ser Asp Val Ala Asn Ala 325 330 335 Val Leu Asp Gly Ala Asp Cys Ile Met Leu Ser Gly Glu Thr Ala Lys 340 345 350 Gly Asp Tyr Pro Leu Glu Ala Val Arg Met Gln His Leu Ile Ala Arg 355 360 365 Glu Ala Glu Ala Ala Ile Tyr His Leu Gln Leu Phe Glu Glu Leu Arg 370 375 380 Arg Leu Ala Pro Ile Thr Ser Asp Pro Thr Glu Ala Thr Ala Val Gly 385 390 395 400 Ala Val Glu Ala Ser Phe Lys Cys Cys Ser Gly Ala Ile Ile Val Leu 405 410 415 Thr Lys Ser Gly Arg Ser Ala His Gln Val Ala Arg Tyr Arg Pro Arg 420 425 430 Ala Pro Ile Ile Ala Val Thr Arg Asn Pro Gln Thr Ala Arg Gln Ala 435 440 445 His Leu Tyr Arg Gly Ile Phe Pro Val Leu Cys Lys Asp Pro Val Gln 450 455 460 Glu Ala Trp Ala Glu Asp Val Asp Leu Arg Val Asn Phe Ala Met Asn 465 470 475 480 Val Gly Lys Ala Arg Gly Phe Phe Lys Lys Gly Asp Val Val Ile Val 485 490 495 Leu Thr Gly Trp Arg Pro Gly Ser Gly Phe Thr Asn Thr Met Arg Val 500 505 510 Val Pro Val Pro 515 23434PRTHomo sapiens 23Met Ser Ile Leu Lys Ile His Ala Arg Glu Ile Phe Asp Ser Arg Gly 1 5 10 15 Asn Pro Thr Val Glu Val Asp Leu Phe Thr Ser Lys Gly Leu Phe Arg 20 25 30 Ala Ala Val Pro Ser Gly Ala Ser Thr Gly Ile Tyr Glu Ala Leu Glu 35 40 45 Leu Arg Asp Asn Asp Lys Thr Arg Tyr Met Gly Lys Gly Val Ser Lys 50 55 60 Ala Val Glu His Ile Asn Lys Thr Ile Ala Pro Ala Leu Val Ser Lys 65 70 75 80 Lys Leu Asn Val Thr Glu Gln Glu Lys Ile Asp Lys Leu Met Ile Glu 85 90 95 Met Asp Gly Thr Glu Asn Lys Ser Lys Phe Gly Ala Asn Ala Ile Leu 100 105 110 Gly Val Ser Leu Ala Val Cys Lys Ala Gly Ala Val Glu Lys Gly Val 115 120 125 Pro Leu Tyr Arg His Ile Ala Asp Leu Ala Gly Asn Ser Glu Val Ile 130 135 140 Leu Pro Val Pro Ala Phe Asn Val Ile Asn Gly Gly Ser His Ala Gly 145 150 155 160 Asn Lys Leu Ala Met Gln Glu Phe Met Ile Leu Pro Val Gly Ala Ala 165 170 175 Asn Phe Arg Glu Ala Met Arg Ile Gly Ala Glu Val Tyr His Asn Leu 180 185 190 Lys Asn Val Ile Lys Glu Lys Tyr Gly Lys Asp Ala Thr Asn Val Gly 195 200 205 Asp Glu Gly Gly Phe Ala Pro Asn Ile Leu Glu Asn Lys Glu Gly Leu 210 215 220 Glu Leu Leu Lys Thr Ala Ile Gly Lys Ala Gly Tyr Thr Asp Lys Val 225 230 235 240 Val Ile Gly Met Asp Val Ala Ala Ser Glu Phe Phe Arg Ser Gly Lys 245 250 255 Tyr Asp Leu Asp Phe Lys Ser Pro Asp Asp Pro Ser Arg Tyr Ile Ser 260 265 270 Pro Asp Gln Leu Ala Asp Leu Tyr Lys Ser Phe Ile Lys Asp Tyr Pro 275 280 285 Val Val Ser Ile Glu Asp Pro Phe Asp Gln Asp Asp Trp Gly Ala Trp 290 295 300 Gln Lys Phe Thr Ala Ser Ala Gly Ile Gln Val Val Gly Asp Asp Leu 305 310 315 320 Thr Val Thr Asn Pro Lys Arg Ile Ala Lys Ala Val Asn Glu Lys Ser 325 330 335 Cys Asn Cys Leu Leu Leu Lys Val Asn Gln Ile Gly Ser Val Thr Glu 340 345 350 Ser Leu Gln Ala Cys Lys Leu Ala Gln Ala Asn Gly Trp Gly Val Met 355 360 365 Val Ser His Arg Ser Gly Glu Thr Glu Asp Thr Phe Ile Ala Asp Leu 370 375 380 Val Val Gly Leu Cys Thr Gly Gln Ile Lys Thr Gly Ala Pro Cys Arg 385 390 395 400 Ser Glu Arg Leu Ala Lys Tyr Asn Gln Leu Leu Arg Ile Glu Glu Glu 405 410 415 Leu Gly Ser Lys Ala Lys Phe Ala Gly Arg Asn Phe Arg Asn Pro Leu 420 425 430 Ala Lys 245890PRTHomo sapiens 24Met Glu Lys Glu Glu Thr Thr Arg Glu Leu Leu Leu Pro Asn Trp Gln 1 5 10 15 Gly Ser Gly Ser His Gly Leu Thr Ile Ala Gln Arg Asp Asp Gly Val 20 25 30 Phe Val Gln Glu Val Thr Gln Asn Ser Pro Ala Ala Arg Thr Gly Val 35 40 45 Val Lys Glu Gly Asp Gln Ile Val Gly Ala Thr Ile Tyr Phe Asp Asn 50 55 60 Leu Gln Ser Gly Glu Val Thr Gln Leu Leu Asn Thr Met Gly His His 65 70 75 80 Thr Val Gly Leu Lys Leu His Arg Lys Gly Asp Arg Ser Pro Glu Pro 85 90 95 Gly Gln Thr Trp Thr Arg Glu Val Phe Ser Ser Cys Ser Ser Glu Val 100 105 110 Val Leu Ser Gly Asp Asp Glu Glu Tyr Gln Arg Ile Tyr Thr Thr Lys 115 120 125 Ile Lys Pro Arg Leu Lys Ser Glu Asp Gly Val Glu Gly Asp Leu Gly 130 135 140 Glu Thr Gln Ser Arg Thr Ile Thr Val Thr Arg Arg Val Thr Ala Tyr 145 150 155 160 Thr Val Asp Val Thr Gly Arg Glu Gly Ala Lys Asp Ile Asp Ile Ser 165 170 175 Ser Pro Glu Phe Lys Ile Lys Ile Pro Arg His Glu Leu Thr Glu Ile 180 185 190 Ser Asn Val Asp Val Glu Thr Gln Ser Gly Lys Thr Val Ile Arg Leu 195 200 205 Pro Ser Gly Ser Gly Ala Ala Ser Pro Thr Gly Ser Ala Val Asp Ile 210 215 220 Arg Ala Gly Ala Ile Ser Ala Ser Gly Pro Glu Leu Gln Gly Ala Gly 225 230 235 240 His Ser Lys Leu Gln Val Thr Met Pro Gly Ile Lys Val Gly Gly Ser 245 250 255 Gly Val Asn Val Asn Ala Lys Gly Leu Asp Leu Gly Gly Arg Gly Gly 260 265 270 Val Gln Val Pro Ala Val Asp Ile Ser Ser Ser Leu Gly Gly Arg Ala 275 280 285 Val Glu Val Gln Gly Pro Ser Leu Glu Ser Gly Asp His Gly Lys Ile 290 295 300 Lys Phe Pro Thr Met Lys Val Pro Lys Phe Gly Val Ser Thr Gly Arg 305 310 315 320 Glu Gly Gln Thr Pro Lys Ala Gly Leu Arg Val Ser Ala Pro Glu Val 325 330 335 Ser Val Gly His Lys Gly Gly Lys Pro Gly Leu Thr Ile Gln Ala Pro 340 345 350 Gln Leu Glu Val Ser Val Pro Ser Ala Asn Ile Glu Gly Leu Glu Gly 355 360 365 Lys Leu Lys Gly Pro Gln Ile Thr Gly Pro Ser Leu Glu Gly Asp Leu 370 375 380 Gly Leu Lys Gly Ala Lys Pro Gln Gly His Ile Gly Val Asp Ala Ser 385 390 395 400 Ala Pro Gln Ile Gly Gly Ser Ile Thr Gly Pro Ser Val Glu Val Gln 405 410 415 Ala Pro Asp Ile Asp Val Gln Gly Pro Gly Ser Lys Leu Asn Val Pro 420 425 430 Lys Met Lys Val Pro Lys Phe Ser Val Ser Gly Ala Lys Gly Glu Glu 435 440 445 Thr Gly Ile Asp Val Thr Leu Pro Thr Gly Glu Val Thr Val Pro Gly 450 455 460 Val Ser Gly Asp Val Ser Leu Pro Glu Ile Ala Thr Gly Gly Leu Glu 465 470 475 480 Gly Lys Met Lys Gly Thr Lys Val Lys Thr Pro Glu Met Ile Ile Gln 485 490 495 Lys Pro Lys Ile Ser Met Gln Asp Val Asp Leu Ser Leu Gly Ser Pro 500 505 510 Lys Leu Lys Gly Asp Ile Lys Val Ser Ala Pro Gly Val Gln Gly Asp 515 520 525 Val Lys Gly Pro Gln Val Ala Leu Lys Gly Ser Arg Val Asp Ile Glu 530 535 540 Thr Pro Asn Leu Glu Gly Thr Leu Thr Gly Pro Arg Leu Gly Ser Pro 545 550 555 560 Ser Gly Lys Thr Gly Thr Cys Arg Ile Ser Met Ser Glu Val Asp Leu 565 570 575 Asn Val Ala Ala Pro Lys Val Lys Gly Gly Val Asp Val Thr Leu Pro 580 585 590 Arg Val Glu Gly Lys Val Lys Val Pro Glu Val Asp Val Arg Gly Pro 595 600 605 Lys Val Asp Val Ser Ala Pro Asp Val Glu Ala His Gly Pro Glu Trp 610 615 620 Asn Leu Lys Met Pro Lys Met Lys Met Pro Thr Phe Ser Thr Pro Gly 625 630 635 640 Ala Lys Gly Glu Gly Pro Asp Val His Met Thr Leu Pro Lys Gly Asp 645 650 655 Ile Ser Ile Ser Gly Pro Lys Val Asn Val Glu Ala Pro Asp Val Asn 660 665 670 Leu Glu Gly Leu Gly Gly Lys Leu Lys Gly Pro Asp Val Lys Leu Pro 675 680 685 Asp Met Ser Val Lys Thr Pro Lys Ile Ser Met Pro Asp Val Asp Leu 690 695 700 His Val Lys Gly Thr Lys Val Lys Gly Glu Tyr Asp Val Thr Val Pro 705 710 715 720 Lys Leu Glu Gly Glu Leu Lys Gly Pro Lys Val Asp Ile Asp Ala Pro 725 730 735 Asp Val Asp Val His Gly Pro Asp Trp His Leu Lys Met Pro Lys Met 740 745 750 Lys Met Pro Lys Phe Ser Val Pro Gly Phe Lys Ala Glu Gly Pro Glu 755 760 765 Val Asp Val Asn Leu Pro Lys Ala Asp Val Asp Ile Ser Gly Pro Lys 770 775 780 Ile Asp Val Thr Ala Pro Asp Val Ser Ile Glu Glu Pro Glu Gly Lys 785 790 795 800 Leu Lys Gly Pro Lys Phe Lys Met Pro Glu Met Asn Ile Lys Val Pro 805 810 815 Lys Ile Ser Met Pro Asp Val Asp Leu His Leu Lys Gly Pro Asn Val 820 825 830 Lys Gly Glu Tyr Asp Val Thr Met Pro Lys Val Glu Ser Glu Ile Lys 835 840 845 Val Pro Asp Val Glu Leu Lys Ser Ala Lys Met Asp Ile Asp Val Pro 850 855 860 Asp Val Glu Val Gln Gly Pro Asp Trp His Leu Lys Met Pro Lys Met 865 870 875 880 Lys Met Pro Lys Phe Ser Met Pro Gly Phe Lys Ala Glu Gly Pro Glu 885 890 895 Val Asp Val Asn Leu Pro Lys Ala Asp Val Asp Ile Ser Gly Pro Lys 900 905 910 Val Gly Val Glu Val Pro Asp Val Asn Ile Glu Gly Pro Glu Gly Lys 915 920 925 Leu Lys Gly Pro Lys Phe Lys Met Pro Glu Met Asn Ile Lys Ala Pro 930 935 940 Lys Ile Ser Met Pro Asp Val Asp Leu His Met Lys Gly Pro Lys Val 945 950 955 960 Lys Gly Glu Tyr Asp Met Thr Val Pro Lys Leu Glu Gly Asp Leu Lys 965 970 975 Gly Pro Lys Val Asp Val Ser Ala Pro Asp Val Glu Met Gln Gly Pro 980 985 990 Asp Trp Asn Leu Lys Met Pro Lys Ile Lys Met Pro Lys Phe Ser Met 995 1000 1005 Pro Ser Leu Lys Gly Glu Gly Pro Glu Phe Asp Val Asn Leu Ser 1010 1015 1020 Lys Ala Asn Val Asp Ile Ser Ala Pro Lys Val Asp Thr Asn Ala 1025 1030 1035 Pro Asp Leu Ser Leu Glu Gly Pro Glu Gly Lys Leu Lys Gly Pro 1040 1045 1050 Lys Phe Lys Met Pro Glu Met His Phe Arg Ala Pro Lys Met Ser 1055 1060 1065 Leu Pro Asp Val Asp Leu Asp Leu Lys Gly Pro Lys Met Lys Gly 1070 1075 1080 Asn Val Asp Ile Ser Ala Pro Lys Ile Glu Gly Glu Met Gln Val 1085 1090 1095 Pro Asp Val Asp Ile Arg Gly Pro Lys Val Asp Ile Lys Ala Pro 1100 1105 1110 Asp Val Glu Gly Gln Gly Leu Asp Trp Ser Leu Lys Ile Pro Lys 1115 1120 1125 Met Lys Met Pro Lys Phe Ser Met Pro Ser Leu Lys Gly Glu Gly 1130 1135 1140 Pro Glu Val Asp Val Asn Leu Pro Lys Ala Asp Val Val Val Ser 1145 1150 1155 Gly Pro Lys Val Asp Ile Glu Ala Pro Asp Val Ser Leu Glu Gly 1160 1165 1170 Pro Glu Gly Lys Leu Lys Gly Pro Lys Phe Lys Met Pro Glu Met 1175 1180 1185 His Phe Lys Thr Pro Lys Ile Ser Met Pro Asp Val Asp Leu His 1190 1195 1200 Leu Lys Gly Pro Lys Val Lys Gly Asp Val Asp Val Ser Val Pro 1205 1210 1215 Lys Val Glu Gly Glu Met Lys Val Pro Asp Val Glu Ile Lys Gly 1220 1225 1230 Pro Lys Met Asp Ile Asp Ala Pro Asp Val Glu Val Gln Gly Pro 1235 1240 1245 Asp Trp His Leu Lys Met Pro Lys Met Lys Met Pro Lys Phe Ser 1250 1255 1260 Met Pro Gly Phe Lys Gly Glu Gly Arg Glu Val Asp Val Asn Leu 1265 1270

1275 Pro Lys Ala Asp Ile Asp Val Ser Gly Pro Lys Val Asp Val Glu 1280 1285 1290 Val Pro Asp Val Ser Leu Glu Gly Pro Glu Gly Lys Leu Lys Gly 1295 1300 1305 Pro Lys Phe Lys Met Pro Glu Met His Phe Lys Ala Pro Lys Ile 1310 1315 1320 Ser Met Pro Asp Val Asp Leu Asn Leu Lys Gly Pro Lys Leu Lys 1325 1330 1335 Gly Asp Val Asp Val Ser Leu Pro Glu Val Glu Gly Glu Met Lys 1340 1345 1350 Val Pro Asp Val Asp Ile Lys Gly Pro Lys Val Asp Ile Ser Ala 1355 1360 1365 Pro Asp Val Asp Val His Gly Pro Asp Trp His Leu Lys Met Pro 1370 1375 1380 Lys Val Lys Met Pro Lys Phe Ser Met Pro Gly Phe Lys Gly Glu 1385 1390 1395 Gly Pro Glu Val Asp Val Lys Leu Pro Lys Ala Asp Val Asp Val 1400 1405 1410 Ser Gly Pro Lys Met Asp Ala Glu Val Pro Asp Val Asn Ile Glu 1415 1420 1425 Gly Pro Asp Ala Lys Leu Lys Gly Pro Lys Phe Lys Met Pro Glu 1430 1435 1440 Met Ser Ile Lys Pro Gln Lys Ile Ser Ile Pro Asp Val Gly Leu 1445 1450 1455 His Leu Lys Gly Pro Lys Met Lys Gly Asp Tyr Asp Val Thr Val 1460 1465 1470 Pro Lys Val Glu Gly Glu Ile Lys Ala Pro Asp Val Asp Ile Lys 1475 1480 1485 Gly Pro Lys Val Asp Ile Asn Ala Pro Asp Val Glu Val His Gly 1490 1495 1500 Pro Asp Trp His Leu Lys Met Pro Lys Val Lys Met Pro Lys Phe 1505 1510 1515 Ser Met Pro Gly Phe Lys Gly Glu Gly Pro Glu Val Asp Met Asn 1520 1525 1530 Leu Pro Lys Ala Asp Leu Gly Val Ser Gly Pro Lys Val Asp Ile 1535 1540 1545 Asp Val Pro Asp Val Asn Leu Glu Ala Pro Glu Gly Lys Leu Lys 1550 1555 1560 Gly Pro Lys Phe Lys Met Pro Ser Met Asn Ile Gln Thr His Lys 1565 1570 1575 Ile Ser Met Pro Asp Val Gly Leu Asn Leu Lys Ala Pro Lys Leu 1580 1585 1590 Lys Thr Asp Val Asp Val Ser Leu Pro Lys Val Glu Gly Asp Leu 1595 1600 1605 Lys Gly Pro Glu Ile Asp Val Lys Ala Pro Lys Met Asp Val Asn 1610 1615 1620 Val Gly Asp Ile Asp Ile Glu Gly Pro Glu Gly Lys Leu Lys Gly 1625 1630 1635 Pro Lys Phe Lys Met Pro Glu Met His Phe Lys Ala Pro Lys Ile 1640 1645 1650 Ser Met Pro Asp Val Asp Leu His Leu Lys Gly Pro Lys Val Lys 1655 1660 1665 Gly Asp Met Asp Val Ser Val Pro Lys Val Glu Gly Glu Met Lys 1670 1675 1680 Val Pro Asp Val Asp Ile Lys Gly Pro Lys Val Asp Ile Asp Ala 1685 1690 1695 Pro Asp Val Glu Val His Asp Pro Asp Trp His Leu Lys Met Pro 1700 1705 1710 Lys Met Lys Met Pro Lys Phe Ser Met Pro Gly Phe Lys Ala Glu 1715 1720 1725 Gly Pro Glu Val Asp Val Asn Leu Pro Lys Ala Asp Ile Asp Val 1730 1735 1740 Ser Gly Pro Ser Val Asp Thr Asp Ala Pro Asp Leu Asp Ile Glu 1745 1750 1755 Gly Pro Glu Gly Lys Leu Lys Gly Ser Lys Phe Lys Met Pro Lys 1760 1765 1770 Leu Asn Ile Lys Ala Pro Lys Val Ser Met Pro Asp Val Asp Leu 1775 1780 1785 Asn Leu Lys Gly Pro Lys Leu Lys Gly Glu Ile Asp Ala Ser Val 1790 1795 1800 Pro Glu Leu Glu Gly Asp Leu Arg Gly Pro Gln Val Asp Val Lys 1805 1810 1815 Gly Pro Phe Val Glu Ala Glu Val Pro Asp Val Asp Leu Glu Cys 1820 1825 1830 Pro Asp Ala Lys Leu Lys Gly Pro Lys Phe Lys Met Pro Glu Met 1835 1840 1845 His Phe Lys Ala Pro Lys Ile Ser Met Pro Asp Val Asp Leu His 1850 1855 1860 Leu Lys Gly Pro Lys Val Lys Gly Asp Ala Asp Val Ser Val Pro 1865 1870 1875 Lys Leu Glu Gly Asp Leu Thr Gly Pro Ser Val Gly Val Glu Val 1880 1885 1890 Pro Asp Val Glu Leu Glu Cys Pro Asp Ala Lys Leu Lys Gly Pro 1895 1900 1905 Lys Phe Lys Met Pro Asp Met His Phe Lys Ala Pro Lys Ile Ser 1910 1915 1920 Met Pro Asp Val Asp Leu His Leu Lys Gly Pro Lys Val Lys Gly 1925 1930 1935 Asp Val Asp Val Ser Val Pro Lys Leu Glu Gly Asp Leu Thr Gly 1940 1945 1950 Pro Ser Val Gly Val Glu Val Pro Asp Val Glu Leu Glu Cys Pro 1955 1960 1965 Asp Ala Lys Leu Lys Gly Pro Lys Phe Lys Met Pro Glu Met His 1970 1975 1980 Phe Lys Thr Pro Lys Ile Ser Met Pro Asp Val Asp Leu His Leu 1985 1990 1995 Lys Gly Pro Lys Val Lys Gly Asp Met Asp Val Ser Val Pro Lys 2000 2005 2010 Val Glu Gly Glu Met Lys Val Pro Asp Val Asp Ile Lys Gly Pro 2015 2020 2025 Lys Met Asp Ile Asp Ala Pro Asp Val Asp Val His Gly Pro Asp 2030 2035 2040 Trp His Leu Lys Met Pro Lys Met Lys Met Pro Lys Phe Ser Met 2045 2050 2055 Pro Gly Phe Lys Ala Glu Gly Pro Glu Val Asp Val Asn Leu Pro 2060 2065 2070 Lys Ala Asp Val Val Val Ser Gly Pro Lys Val Asp Val Glu Val 2075 2080 2085 Pro Asp Val Ser Leu Glu Gly Pro Glu Gly Lys Leu Lys Gly Pro 2090 2095 2100 Lys Leu Lys Met Pro Glu Met His Phe Lys Ala Pro Lys Ile Ser 2105 2110 2115 Met Pro Asp Val Asp Leu His Leu Lys Gly Pro Lys Val Lys Gly 2120 2125 2130 Asp Val Asp Val Ser Leu Pro Lys Leu Glu Gly Asp Leu Thr Gly 2135 2140 2145 Pro Ser Val Asp Val Glu Val Pro Asp Val Glu Leu Glu Cys Pro 2150 2155 2160 Asp Ala Lys Leu Lys Gly Pro Lys Phe Lys Met Pro Glu Met His 2165 2170 2175 Phe Lys Thr Pro Lys Ile Ser Met Pro Asp Val Asn Leu Asn Leu 2180 2185 2190 Lys Gly Pro Lys Val Lys Gly Asp Met Asp Val Ser Val Pro Lys 2195 2200 2205 Val Glu Gly Glu Met Lys Val Pro Asp Val Asp Ile Arg Gly Pro 2210 2215 2220 Lys Val Asp Ile Asp Ala Pro Asp Val Asp Val His Gly Pro Asp 2225 2230 2235 Trp His Leu Lys Met Pro Lys Met Lys Met Pro Lys Phe Ser Met 2240 2245 2250 Pro Gly Phe Lys Gly Glu Gly Pro Glu Val Asp Val Asn Leu Pro 2255 2260 2265 Lys Ala Asp Val Asp Val Ser Gly Pro Lys Val Asp Val Glu Val 2270 2275 2280 Pro Asp Val Ser Leu Glu Gly Pro Glu Gly Lys Leu Lys Gly Pro 2285 2290 2295 Lys Phe Lys Met Pro Glu Met His Phe Lys Thr Pro Lys Ile Ser 2300 2305 2310 Met Pro Asp Val Asp Phe Asn Leu Lys Gly Pro Lys Ile Lys Gly 2315 2320 2325 Asp Val Asp Val Ser Ala Pro Lys Leu Glu Gly Glu Leu Lys Gly 2330 2335 2340 Pro Glu Leu Asp Val Lys Gly Pro Lys Leu Asp Ala Asp Met Pro 2345 2350 2355 Glu Val Ala Val Glu Gly Pro Asn Gly Lys Trp Lys Thr Pro Lys 2360 2365 2370 Phe Lys Met Pro Asp Met His Phe Lys Ala Pro Lys Ile Ser Met 2375 2380 2385 Pro Asp Leu Asp Leu His Leu Lys Ser Pro Lys Ala Lys Gly Glu 2390 2395 2400 Val Asp Val Asp Val Pro Lys Leu Glu Gly Asp Leu Lys Gly Pro 2405 2410 2415 His Val Asp Val Ser Gly Pro Asp Ile Asp Ile Glu Gly Pro Glu 2420 2425 2430 Gly Lys Leu Lys Gly Pro Lys Phe Lys Met Pro Asp Met His Phe 2435 2440 2445 Lys Ala Pro Asn Ile Ser Met Pro Asp Val Asp Leu Asn Leu Lys 2450 2455 2460 Gly Pro Lys Ile Lys Gly Asp Val Asp Val Ser Val Pro Glu Val 2465 2470 2475 Glu Gly Lys Leu Glu Val Pro Asp Met Asn Ile Arg Gly Pro Lys 2480 2485 2490 Val Asp Val Asn Ala Pro Asp Val Gln Ala Pro Asp Trp His Leu 2495 2500 2505 Lys Met Pro Lys Met Lys Met Pro Lys Phe Ser Met Pro Gly Phe 2510 2515 2520 Lys Ala Glu Gly Pro Glu Val Asp Val Asn Leu Pro Lys Ala Asp 2525 2530 2535 Val Asp Ile Ser Gly Pro Lys Val Asp Ile Glu Gly Pro Asp Val 2540 2545 2550 Asn Ile Glu Gly Pro Glu Gly Lys Leu Lys Gly Pro Lys Leu Lys 2555 2560 2565 Met Pro Glu Met Asn Ile Lys Ala Pro Lys Ile Ser Met Pro Asp 2570 2575 2580 Phe Asp Leu His Leu Lys Gly Pro Lys Val Lys Gly Asp Val Asp 2585 2590 2595 Val Ser Leu Pro Lys Val Glu Gly Asp Leu Lys Gly Pro Glu Val 2600 2605 2610 Asp Ile Lys Gly Pro Lys Val Asp Ile Asn Ala Pro Asp Val Gly 2615 2620 2625 Val Gln Gly Pro Asp Trp His Leu Lys Met Pro Lys Val Lys Met 2630 2635 2640 Pro Lys Phe Ser Met Pro Gly Phe Lys Gly Glu Gly Pro Asp Gly 2645 2650 2655 Asp Val Lys Leu Pro Lys Ala Asp Ile Asp Val Ser Gly Pro Lys 2660 2665 2670 Val Asp Ile Glu Gly Pro Asp Val Asn Ile Glu Gly Pro Glu Gly 2675 2680 2685 Lys Leu Lys Gly Pro Lys Phe Lys Met Pro Glu Met Asn Ile Lys 2690 2695 2700 Ala Pro Lys Ile Ser Met Pro Asp Ile Asp Leu Asn Leu Lys Gly 2705 2710 2715 Pro Lys Val Lys Gly Asp Val Asp Val Ser Leu Pro Lys Val Glu 2720 2725 2730 Gly Asp Leu Lys Gly Pro Glu Val Asp Ile Lys Gly Pro Lys Val 2735 2740 2745 Asp Ile Asp Ala Pro Asp Val Asp Val His Gly Pro Asp Trp His 2750 2755 2760 Leu Lys Met Pro Lys Ile Lys Met Pro Lys Ile Ser Met Pro Gly 2765 2770 2775 Phe Lys Gly Glu Gly Pro Asp Val Asp Val Asn Leu Pro Lys Ala 2780 2785 2790 Asp Ile Asp Val Ser Gly Pro Lys Val Asp Val Glu Cys Pro Asp 2795 2800 2805 Val Asn Ile Glu Gly Pro Glu Gly Lys Trp Lys Ser Pro Lys Phe 2810 2815 2820 Lys Met Pro Glu Met His Phe Lys Thr Pro Lys Ile Ser Met Pro 2825 2830 2835 Asp Ile Asp Leu Asn Leu Thr Gly Pro Lys Ile Lys Gly Asp Val 2840 2845 2850 Asp Val Thr Gly Pro Lys Val Glu Gly Asp Leu Lys Gly Pro Glu 2855 2860 2865 Val Asp Leu Lys Gly Pro Lys Val Asp Ile Asp Val Pro Asp Val 2870 2875 2880 Asn Val Gln Gly Pro Asp Trp His Leu Lys Met Pro Lys Met Lys 2885 2890 2895 Met Pro Lys Phe Ser Met Pro Gly Phe Lys Ala Glu Gly Pro Glu 2900 2905 2910 Val Asp Val Asn Leu Pro Lys Ala Asp Val Asp Val Ser Gly Pro 2915 2920 2925 Lys Val Asp Val Glu Gly Pro Asp Val Asn Ile Glu Gly Pro Glu 2930 2935 2940 Gly Lys Leu Lys Gly Pro Lys Phe Lys Met Pro Glu Met Asn Ile 2945 2950 2955 Lys Ala Pro Lys Ile Pro Met Pro Asp Phe Asp Leu His Leu Lys 2960 2965 2970 Gly Pro Lys Val Lys Gly Asp Val Asp Ile Ser Leu Pro Lys Val 2975 2980 2985 Glu Gly Asp Leu Lys Gly Pro Glu Val Asp Ile Arg Gly Pro Gln 2990 2995 3000 Val Asp Ile Asp Val Pro Asp Val Gly Val Gln Gly Pro Asp Trp 3005 3010 3015 His Leu Lys Met Pro Lys Val Lys Met Pro Lys Phe Ser Met Pro 3020 3025 3030 Gly Phe Lys Gly Glu Gly Pro Asp Val Asp Val Asn Leu Pro Lys 3035 3040 3045 Ala Asp Leu Asp Val Ser Gly Pro Lys Val Asp Ile Asp Val Pro 3050 3055 3060 Asp Val Asn Ile Glu Gly Pro Glu Gly Lys Leu Lys Gly Pro Lys 3065 3070 3075 Phe Lys Met Pro Glu Met Asn Ile Lys Ala Pro Lys Ile Ser Met 3080 3085 3090 Pro Asp Ile Asp Leu Asn Leu Lys Gly Pro Lys Val Lys Gly Asp 3095 3100 3105 Met Asp Val Ser Leu Pro Lys Val Glu Gly Asp Met Lys Val Pro 3110 3115 3120 Asp Val Asp Ile Lys Gly Pro Lys Val Asp Ile Asn Ala Pro Asp 3125 3130 3135 Val Asp Val Gln Gly Pro Asp Trp His Leu Lys Met Pro Lys Ile 3140 3145 3150 Lys Met Pro Lys Ile Ser Met Pro Gly Phe Lys Gly Glu Gly Pro 3155 3160 3165 Glu Val Asp Val Asn Leu Pro Lys Ala Asp Leu Asp Val Ser Gly 3170 3175 3180 Pro Lys Val Asp Val Asp Val Pro Asp Val Asn Ile Glu Gly Pro 3185 3190 3195 Asp Ala Lys Leu Lys Gly Pro Lys Phe Lys Met Pro Glu Met Asn 3200 3205 3210 Ile Lys Ala Pro Lys Ile Ser Met Pro Asp Leu Asp Leu Asn Leu 3215 3220 3225 Lys Gly Pro Lys Met Lys Gly Glu Val Asp Val Ser Leu Ala Asn 3230 3235 3240 Val Glu Gly Asp Leu Lys Gly Pro Ala Leu Asp Ile Lys Gly Pro 3245 3250 3255 Lys Ile Asp Val Asp Ala Pro Asp Ile Asp Ile His Gly Pro Asp 3260 3265 3270 Ala Lys Leu Lys Gly Pro Lys Leu Lys Met Pro Asp Met His Val 3275 3280 3285 Asn Met Pro Lys Ile Ser Met Pro Glu Ile Asp Leu Asn Leu Lys 3290 3295 3300 Gly Ser Lys Leu Lys Gly Asp Val Asp Val Ser Gly Pro Lys Leu 3305 3310 3315 Glu Gly Asp Ile Lys Ala Pro Ser Leu Asp Ile Lys Gly Pro Glu 3320 3325 3330 Val Asp Val Ser Gly Pro Lys Leu Asn Ile Glu Gly Lys Ser Lys 3335 3340 3345 Lys Ser Arg Phe Lys Leu Pro Lys Phe Asn Phe Ser Gly Ser Lys 3350 3355 3360 Val Gln Thr Pro Glu Val Asp Val Lys Gly Lys Lys Pro Asp Ile 3365 3370 3375 Asp Ile Thr Gly Pro Lys Val Asp Ile Asn Ala Pro Asp Val Glu 3380 3385 3390 Val Gln Gly Lys Val Lys Gly Ser Lys Phe Lys Met Pro Phe Leu 3395 3400 3405 Ser Ile Ser Ser Pro Lys Val Ser Met Pro Asp Val Glu Leu Asn 3410 3415 3420 Leu Lys Ser Pro Lys Val Lys Gly Asp Leu Asp Ile Ala Gly Pro 3425 3430 3435 Asn Leu Glu Gly Asp Phe Lys Gly Pro Lys Val Asp Ile Lys Ala 3440 3445 3450 Pro Glu Val Asn Leu Asn Ala Pro Asp Val Asp Val His Gly Pro 3455 3460 3465 Asp Trp Asn Leu Lys Met Pro

Lys Met Lys Met Pro Lys Phe Ser 3470 3475 3480 Val Ser Gly Leu Lys Ala Glu Gly Pro Asp Val Ala Val Asp Leu 3485 3490 3495 Pro Lys Gly Asp Ile Asn Ile Glu Gly Pro Ser Met Asn Ile Glu 3500 3505 3510 Gly Pro Asp Leu Asn Val Glu Gly Pro Glu Gly Gly Leu Lys Gly 3515 3520 3525 Pro Lys Phe Lys Met Pro Asp Met Asn Ile Lys Ala Pro Lys Ile 3530 3535 3540 Ser Met Pro Asp Ile Asp Leu Asn Leu Lys Gly Pro Lys Val Lys 3545 3550 3555 Gly Asp Val Asp Ile Ser Leu Pro Lys Leu Glu Gly Asp Leu Lys 3560 3565 3570 Gly Pro Glu Val Asp Ile Lys Gly Pro Lys Val Asp Ile Asn Ala 3575 3580 3585 Pro Asp Val Asp Val His Gly Pro Asp Trp His Leu Lys Met Pro 3590 3595 3600 Lys Val Lys Met Pro Lys Phe Ser Met Pro Gly Phe Lys Gly Glu 3605 3610 3615 Gly Pro Glu Val Asp Val Thr Leu Pro Lys Ala Asp Ile Asp Ile 3620 3625 3630 Ser Gly Pro Asn Val Asp Val Asp Val Pro Asp Val Asn Ile Glu 3635 3640 3645 Gly Pro Asp Ala Lys Leu Lys Gly Pro Lys Phe Lys Met Pro Glu 3650 3655 3660 Met Asn Ile Lys Ala Pro Lys Ile Ser Met Pro Asp Phe Asp Leu 3665 3670 3675 Asn Leu Lys Gly Pro Lys Met Lys Gly Asp Val Val Val Ser Leu 3680 3685 3690 Pro Lys Val Glu Gly Asp Leu Lys Gly Pro Glu Val Asp Ile Lys 3695 3700 3705 Gly Pro Lys Val Asp Ile Asp Thr Pro Asp Ile Asn Ile Glu Gly 3710 3715 3720 Ser Glu Gly Lys Phe Lys Gly Pro Lys Phe Lys Ile Pro Glu Met 3725 3730 3735 His Leu Lys Ala Pro Lys Ile Ser Met Pro Asp Ile Asp Leu Asn 3740 3745 3750 Leu Lys Gly Pro Lys Val Lys Gly Asp Val Asp Val Ser Leu Pro 3755 3760 3765 Lys Met Glu Gly Asp Leu Lys Gly Pro Glu Val Asp Ile Lys Gly 3770 3775 3780 Pro Lys Val Asp Ile Asn Ala Pro Asp Val Asp Val Gln Gly Pro 3785 3790 3795 Asp Trp His Leu Lys Met Pro Lys Val Lys Met Pro Lys Phe Ser 3800 3805 3810 Met Pro Gly Phe Lys Gly Glu Gly Pro Asp Val Asp Val Asn Leu 3815 3820 3825 Pro Lys Ala Asp Leu Asp Val Ser Gly Pro Lys Val Asp Ile Asp 3830 3835 3840 Val Pro Asp Val Asn Ile Glu Gly Pro Glu Gly Lys Leu Lys Gly 3845 3850 3855 Pro Lys Phe Lys Met Pro Glu Met Asn Ile Lys Ala Pro Lys Ile 3860 3865 3870 Ser Met Pro Asp Ile Asp Leu Asn Leu Lys Gly Pro Lys Val Lys 3875 3880 3885 Gly Asp Met Asp Val Ser Leu Pro Lys Val Glu Gly Asp Met Gln 3890 3895 3900 Val Pro Asp Leu Asp Ile Lys Gly Pro Lys Val Asp Ile Asn Ala 3905 3910 3915 Pro Asp Val Asp Val Arg Gly Pro Asp Trp His Leu Lys Met Pro 3920 3925 3930 Lys Ile Lys Met Pro Lys Ile Ser Met Pro Gly Phe Lys Gly Glu 3935 3940 3945 Gly Pro Glu Val Asp Val Asn Leu Pro Lys Ala Asp Leu Asp Val 3950 3955 3960 Ser Gly Pro Lys Val Asp Val Asp Val Pro Asp Val Asn Ile Glu 3965 3970 3975 Gly Pro Asp Ala Lys Leu Lys Gly Pro Lys Phe Lys Met Pro Glu 3980 3985 3990 Met Asn Ile Lys Ala Pro Lys Ile Ser Met Pro Asp Phe Asp Leu 3995 4000 4005 His Leu Lys Gly Pro Lys Val Lys Gly Asp Val Asp Val Ser Leu 4010 4015 4020 Pro Lys Met Glu Gly Asp Leu Lys Ala Pro Glu Val Asp Ile Lys 4025 4030 4035 Gly Pro Lys Val Asp Ile Asp Ala Pro Asp Val Asp Val His Gly 4040 4045 4050 Pro Asp Trp His Leu Lys Met Pro Lys Val Lys Met Pro Lys Phe 4055 4060 4065 Ser Met Pro Gly Phe Lys Gly Glu Gly Pro Glu Val Asp Val Asn 4070 4075 4080 Leu Pro Lys Ala Asp Ile Asp Val Ser Gly Pro Lys Val Asp Ile 4085 4090 4095 Asp Thr Pro Asp Ile Asp Ile His Gly Pro Glu Gly Lys Leu Lys 4100 4105 4110 Gly Pro Lys Phe Lys Met Pro Asp Leu His Leu Lys Ala Pro Lys 4115 4120 4125 Ile Ser Met Pro Glu Val Asp Leu Asn Leu Lys Gly Pro Lys Met 4130 4135 4140 Lys Gly Asp Val Asp Val Ser Leu Pro Lys Val Glu Gly Asp Leu 4145 4150 4155 Lys Gly Pro Glu Val Asp Ile Lys Gly Pro Lys Val Asp Ile Asp 4160 4165 4170 Val Pro Asp Val Asp Val Gln Gly Pro Asp Trp His Leu Lys Met 4175 4180 4185 Pro Lys Val Lys Met Pro Lys Phe Ser Met Pro Gly Phe Lys Gly 4190 4195 4200 Glu Gly Pro Asp Val Asp Val Asn Leu Pro Lys Ala Asp Leu Asp 4205 4210 4215 Val Ser Gly Pro Lys Val Asp Ile Asp Val Pro Asp Val Asn Ile 4220 4225 4230 Glu Gly Pro Asp Ala Lys Leu Lys Gly Pro Lys Phe Lys Met Pro 4235 4240 4245 Glu Met Asn Ile Lys Ala Pro Lys Ile Ser Met Pro Asp Phe Asp 4250 4255 4260 Leu His Leu Lys Gly Pro Lys Val Lys Gly Asp Val Asp Val Ser 4265 4270 4275 Leu Pro Lys Val Glu Gly Asp Leu Lys Gly Pro Glu Val Asp Ile 4280 4285 4290 Lys Gly Pro Lys Val Asp Ile Asp Ala Pro Asp Val Asp Val His 4295 4300 4305 Gly Pro Asp Trp His Leu Lys Met Pro Lys Val Lys Met Pro Lys 4310 4315 4320 Phe Ser Met Pro Gly Phe Lys Gly Glu Gly Pro Asp Val Asp Val 4325 4330 4335 Thr Leu Pro Lys Ala Asp Ile Glu Ile Ser Gly Pro Lys Val Asp 4340 4345 4350 Ile Asp Ala Pro Asp Val Ser Ile Glu Gly Pro Asp Ala Lys Leu 4355 4360 4365 Lys Gly Pro Lys Phe Lys Met Pro Glu Met Asn Ile Lys Ala Pro 4370 4375 4380 Lys Ile Ser Met Pro Asp Ile Asp Phe Asn Leu Lys Gly Pro Lys 4385 4390 4395 Val Lys Gly Asp Val Asp Val Ser Leu Pro Lys Val Glu Gly Asp 4400 4405 4410 Leu Lys Gly Pro Glu Ile Asp Ile Lys Gly Pro Ser Leu Asp Ile 4415 4420 4425 Asp Thr Pro Asp Val Asn Ile Glu Gly Pro Glu Gly Lys Leu Lys 4430 4435 4440 Gly Pro Lys Phe Lys Met Pro Glu Met Asn Ile Lys Ala Pro Lys 4445 4450 4455 Ile Ser Met Pro Asp Phe Asp Leu His Leu Lys Gly Pro Lys Val 4460 4465 4470 Lys Gly Asp Val Asp Val Ser Leu Pro Lys Val Glu Ser Asp Leu 4475 4480 4485 Lys Gly Pro Glu Val Asp Ile Glu Gly Pro Glu Gly Lys Leu Lys 4490 4495 4500 Gly Pro Lys Phe Lys Met Pro Asp Val His Phe Lys Ser Pro Gln 4505 4510 4515 Ile Ser Met Ser Asp Ile Asp Leu Asn Leu Lys Gly Pro Lys Ile 4520 4525 4530 Lys Gly Asp Met Asp Ile Ser Val Pro Lys Leu Glu Gly Asp Leu 4535 4540 4545 Lys Gly Pro Lys Val Asp Val Lys Gly Pro Lys Val Gly Ile Asp 4550 4555 4560 Thr Pro Asp Ile Asp Ile His Gly Pro Glu Gly Lys Leu Lys Gly 4565 4570 4575 Pro Lys Phe Lys Met Pro Asp Leu His Leu Lys Ala Pro Lys Ile 4580 4585 4590 Ser Met Pro Glu Val Asp Leu Asn Leu Lys Gly Pro Lys Val Lys 4595 4600 4605 Gly Asp Met Asp Ile Ser Leu Pro Lys Val Glu Gly Asp Leu Lys 4610 4615 4620 Gly Pro Glu Val Asp Ile Arg Asp Pro Lys Val Asp Ile Asp Val 4625 4630 4635 Pro Asp Val Asp Val Gln Gly Pro Asp Trp His Leu Lys Met Pro 4640 4645 4650 Lys Val Lys Met Pro Lys Phe Ser Met Pro Gly Phe Lys Gly Glu 4655 4660 4665 Gly Pro Asp Val Asp Val Asn Leu Pro Lys Ala Asp Ile Asp Val 4670 4675 4680 Ser Gly Pro Lys Val Asp Val Asp Val Pro Asp Val Asn Ile Glu 4685 4690 4695 Gly Pro Asp Ala Lys Leu Lys Gly Pro Lys Phe Lys Met Pro Glu 4700 4705 4710 Met Ser Ile Lys Ala Pro Lys Ile Ser Met Pro Asp Ile Asp Leu 4715 4720 4725 Asn Leu Lys Gly Pro Lys Val Lys Gly Asp Val Asp Val Thr Leu 4730 4735 4740 Pro Lys Val Glu Gly Asp Leu Lys Gly Pro Glu Ala Asp Ile Lys 4745 4750 4755 Gly Pro Lys Val Asp Ile Asn Thr Pro Asp Val Asp Val His Gly 4760 4765 4770 Pro Asp Trp His Leu Lys Met Pro Lys Val Lys Met Pro Lys Phe 4775 4780 4785 Ser Met Pro Gly Phe Lys Gly Glu Gly Pro Asp Val Asp Val Ser 4790 4795 4800 Leu Pro Lys Ala Asp Ile Asp Val Ser Gly Pro Lys Val Asp Val 4805 4810 4815 Asp Ile Pro Asp Val Asn Ile Glu Gly Pro Asp Ala Lys Leu Lys 4820 4825 4830 Gly Pro Lys Phe Lys Met Pro Glu Ile Asn Ile Lys Ala Pro Lys 4835 4840 4845 Ile Ser Ile Pro Asp Val Asp Leu Asp Leu Lys Gly Pro Lys Val 4850 4855 4860 Lys Gly Asp Phe Asp Val Ser Val Pro Lys Val Glu Gly Thr Leu 4865 4870 4875 Lys Gly Pro Glu Val Asp Leu Lys Gly Pro Arg Leu Asp Phe Glu 4880 4885 4890 Gly Pro Asp Ala Lys Leu Ser Gly Pro Ser Leu Lys Met Pro Ser 4895 4900 4905 Leu Glu Ile Ser Ala Pro Lys Val Thr Ala Pro Asp Val Asp Leu 4910 4915 4920 His Leu Lys Ala Pro Lys Ile Gly Phe Ser Gly Pro Lys Leu Glu 4925 4930 4935 Gly Gly Glu Val Asp Leu Lys Gly Pro Lys Val Glu Ala Pro Ser 4940 4945 4950 Leu Asp Val His Met Asp Ser Pro Asp Ile Asn Ile Glu Gly Pro 4955 4960 4965 Asp Val Lys Ile Pro Lys Phe Lys Lys Pro Lys Phe Gly Phe Gly 4970 4975 4980 Ala Lys Ser Pro Lys Ala Asp Ile Lys Ser Pro Ser Leu Asp Val 4985 4990 4995 Thr Val Pro Glu Ala Glu Leu Asn Leu Glu Thr Pro Glu Ile Ser 5000 5005 5010 Val Gly Gly Lys Gly Lys Lys Ser Lys Phe Lys Met Pro Lys Ile 5015 5020 5025 His Met Ser Gly Pro Lys Ile Lys Ala Lys Lys Gln Gly Phe Asp 5030 5035 5040 Leu Asn Val Pro Gly Gly Glu Ile Asp Ala Ser Leu Lys Ala Pro 5045 5050 5055 Asp Val Asp Val Asn Ile Ala Gly Pro Asp Ala Ala Leu Lys Val 5060 5065 5070 Asp Val Lys Ser Pro Lys Thr Lys Lys Thr Met Phe Gly Lys Met 5075 5080 5085 Tyr Phe Pro Asp Val Glu Phe Asp Ile Lys Ser Pro Lys Phe Lys 5090 5095 5100 Ala Glu Ala Pro Leu Pro Ser Pro Lys Leu Glu Gly Glu Leu Gln 5105 5110 5115 Ala Pro Asp Leu Glu Leu Ser Leu Pro Ala Ile His Val Glu Gly 5120 5125 5130 Leu Asp Ile Lys Ala Lys Ala Pro Lys Val Lys Met Pro Asp Val 5135 5140 5145 Asp Ile Ser Val Pro Lys Ile Glu Gly Asp Leu Lys Gly Pro Lys 5150 5155 5160 Val Gln Ala Asn Leu Gly Ala Pro Asp Ile Asn Ile Glu Gly Leu 5165 5170 5175 Asp Ala Lys Val Lys Thr Pro Ser Phe Gly Ile Ser Ala Pro Gln 5180 5185 5190 Val Ser Ile Pro Asp Val Asn Val Asn Leu Lys Gly Pro Lys Ile 5195 5200 5205 Lys Gly Asp Val Pro Ser Val Gly Leu Glu Gly Pro Asp Val Asp 5210 5215 5220 Leu Gln Gly Pro Glu Ala Lys Ile Lys Phe Pro Lys Phe Ser Met 5225 5230 5235 Pro Lys Ile Gly Ile Pro Gly Val Lys Met Glu Gly Gly Gly Ala 5240 5245 5250 Glu Val His Ala Gln Leu Pro Ser Leu Glu Gly Asp Leu Arg Gly 5255 5260 5265 Pro Asp Val Lys Leu Glu Gly Pro Asp Val Ser Leu Lys Gly Pro 5270 5275 5280 Gly Val Asp Leu Pro Ser Val Asn Leu Ser Met Pro Lys Val Ser 5285 5290 5295 Gly Pro Asp Leu Asp Leu Asn Leu Lys Gly Pro Ser Leu Lys Gly 5300 5305 5310 Asp Leu Asp Ala Ser Val Pro Ser Met Lys Val His Ala Pro Gly 5315 5320 5325 Leu Asn Leu Ser Gly Val Gly Gly Lys Met Gln Val Gly Gly Asp 5330 5335 5340 Gly Val Lys Val Pro Gly Ile Asp Ala Thr Thr Lys Leu Asn Val 5345 5350 5355 Gly Ala Pro Asp Val Thr Leu Arg Gly Pro Ser Leu Gln Gly Asp 5360 5365 5370 Leu Ala Val Ser Gly Asp Ile Lys Cys Pro Lys Val Ser Val Gly 5375 5380 5385 Ala Pro Asp Leu Ser Leu Glu Ala Ser Glu Gly Ser Ile Lys Leu 5390 5395 5400 Pro Lys Met Lys Leu Pro Gln Phe Gly Ile Ser Thr Pro Gly Ser 5405 5410 5415 Asp Leu His Val Asn Ala Lys Gly Pro Gln Val Ser Gly Glu Leu 5420 5425 5430 Lys Gly Pro Gly Val Asp Val Asn Leu Lys Gly Pro Arg Ile Ser 5435 5440 5445 Ala Pro Asn Val Asp Phe Asn Leu Glu Gly Pro Lys Val Lys Gly 5450 5455 5460 Ser Leu Gly Ala Thr Gly Glu Ile Lys Gly Pro Thr Val Gly Gly 5465 5470 5475 Gly Leu Pro Gly Ile Gly Val Gln Gly Leu Glu Gly Asn Leu Gln 5480 5485 5490 Met Pro Gly Ile Lys Ser Ser Gly Cys Asp Val Asn Leu Pro Gly 5495 5500 5505 Val Asn Val Lys Leu Pro Thr Gly Gln Ile Ser Gly Pro Glu Ile 5510 5515 5520 Lys Gly Gly Leu Lys Gly Ser Glu Val Gly Phe His Gly Ala Ala 5525 5530 5535 Pro Asp Ile Ser Val Lys Gly Pro Ala Phe Asn Met Ala Ser Pro 5540 5545 5550 Glu Ser Asp Phe Gly Ile Asn Leu Lys Gly Pro Lys Ile Lys Gly 5555 5560 5565 Gly Ala Asp Val Ser Gly Gly Val Ser Ala Pro Asp Ile Ser Leu 5570 5575 5580 Gly Glu Gly His Leu Ser Val Lys Gly Ser Gly Gly Glu Trp Lys 5585 5590 5595 Gly Pro Gln Val Ser Ser Ala Leu Asn Leu Asp Thr Ser Lys Phe 5600 5605 5610 Ala Gly Gly Leu His Phe Ser Gly Pro Lys Val Glu Gly Gly Val 5615 5620 5625 Lys Gly Gly Gln Ile Gly Leu Gln Ala Pro Gly Leu Ser Val Ser 5630 5635 5640 Gly Pro Gln Gly His Leu Glu Ser Gly Ser Gly Lys Val Thr Phe 5645 5650 5655 Pro Lys Met Lys Ile Pro Lys Phe Thr Phe Ser Gly Arg Glu Leu 5660

5665 5670 Val Gly Arg Glu Met Gly Val Asp Val His Phe Pro Lys Ala Glu 5675 5680 5685 Ala Ser Ile Gln Ala Gly Ala Gly Asp Gly Glu Trp Glu Glu Ser 5690 5695 5700 Glu Val Lys Leu Lys Lys Ser Lys Ile Lys Met Pro Lys Phe Asn 5705 5710 5715 Phe Ser Lys Pro Lys Gly Lys Gly Gly Val Thr Gly Ser Pro Glu 5720 5725 5730 Ala Ser Ile Ser Gly Ser Lys Gly Asp Leu Lys Ser Ser Lys Ala 5735 5740 5745 Ser Leu Gly Ser Leu Glu Gly Glu Ala Glu Ala Glu Ala Ser Ser 5750 5755 5760 Pro Lys Gly Lys Phe Ser Leu Phe Lys Ser Lys Lys Pro Arg His 5765 5770 5775 Arg Ser Asn Ser Phe Ser Asp Glu Arg Glu Phe Ser Gly Pro Ser 5780 5785 5790 Thr Pro Thr Gly Thr Leu Glu Phe Glu Gly Gly Glu Val Ser Leu 5795 5800 5805 Glu Gly Gly Lys Val Lys Gly Lys His Gly Lys Leu Lys Phe Gly 5810 5815 5820 Thr Phe Gly Gly Leu Gly Ser Lys Ser Lys Gly His Tyr Glu Val 5825 5830 5835 Thr Gly Ser Asp Asp Glu Thr Gly Lys Leu Gln Gly Ser Gly Val 5840 5845 5850 Ser Leu Ala Ser Lys Lys Ser Arg Leu Ser Ser Ser Ser Ser Asn 5855 5860 5865 Asp Ser Gly Asn Lys Val Gly Ile Gln Leu Pro Glu Val Glu Leu 5870 5875 5880 Ser Val Ser Thr Lys Lys Glu 5885 5890 25646PRTHomo sapiens 25Met Ser Lys Gly Pro Ala Val Gly Ile Asp Leu Gly Thr Thr Tyr Ser 1 5 10 15 Cys Val Gly Val Phe Gln His Gly Lys Val Glu Ile Ile Ala Asn Asp 20 25 30 Gln Gly Asn Arg Thr Thr Pro Ser Tyr Val Ala Phe Thr Asp Thr Glu 35 40 45 Arg Leu Ile Gly Asp Ala Ala Lys Asn Gln Val Ala Met Asn Pro Thr 50 55 60 Asn Thr Val Phe Asp Ala Lys Arg Leu Ile Gly Arg Arg Phe Asp Asp 65 70 75 80 Ala Val Val Gln Ser Asp Met Lys His Trp Pro Phe Met Val Val Asn 85 90 95 Asp Ala Gly Arg Pro Lys Val Gln Val Glu Tyr Lys Gly Glu Thr Lys 100 105 110 Ser Phe Tyr Pro Glu Glu Val Ser Ser Met Val Leu Thr Lys Met Lys 115 120 125 Glu Ile Ala Glu Ala Tyr Leu Gly Lys Thr Val Thr Asn Ala Val Val 130 135 140 Thr Val Pro Ala Tyr Phe Asn Asp Ser Gln Arg Gln Ala Thr Lys Asp 145 150 155 160 Ala Gly Thr Ile Ala Gly Leu Asn Val Leu Arg Ile Ile Asn Glu Pro 165 170 175 Thr Ala Ala Ala Ile Ala Tyr Gly Leu Asp Lys Lys Val Gly Ala Glu 180 185 190 Arg Asn Val Leu Ile Phe Asp Leu Gly Gly Gly Thr Phe Asp Val Ser 195 200 205 Ile Leu Thr Ile Glu Asp Gly Ile Phe Glu Val Lys Ser Thr Ala Gly 210 215 220 Asp Thr His Leu Gly Gly Glu Asp Phe Asp Asn Arg Met Val Asn His 225 230 235 240 Phe Ile Ala Glu Phe Lys Arg Lys His Lys Lys Asp Ile Ser Glu Asn 245 250 255 Lys Arg Ala Val Arg Arg Leu Arg Thr Ala Cys Glu Arg Ala Lys Arg 260 265 270 Thr Leu Ser Ser Ser Thr Gln Ala Ser Ile Glu Ile Asp Ser Leu Tyr 275 280 285 Glu Gly Ile Asp Phe Tyr Thr Ser Ile Thr Arg Ala Arg Phe Glu Glu 290 295 300 Leu Asn Ala Asp Leu Phe Arg Gly Thr Leu Asp Pro Val Glu Lys Ala 305 310 315 320 Leu Arg Asp Ala Lys Leu Asp Lys Ser Gln Ile His Asp Ile Val Leu 325 330 335 Val Gly Gly Ser Thr Arg Ile Pro Lys Ile Gln Lys Leu Leu Gln Asp 340 345 350 Phe Phe Asn Gly Lys Glu Leu Asn Lys Ser Ile Asn Pro Asp Glu Ala 355 360 365 Val Ala Tyr Gly Ala Ala Val Gln Ala Ala Ile Leu Ser Gly Asp Lys 370 375 380 Ser Glu Asn Val Gln Asp Leu Leu Leu Leu Asp Val Thr Pro Leu Ser 385 390 395 400 Leu Gly Ile Glu Thr Ala Gly Gly Val Met Thr Val Leu Ile Lys Arg 405 410 415 Asn Thr Thr Ile Pro Thr Lys Gln Thr Gln Thr Phe Thr Thr Tyr Ser 420 425 430 Asp Asn Gln Pro Gly Val Leu Ile Gln Val Tyr Glu Gly Glu Arg Ala 435 440 445 Met Thr Lys Asp Asn Asn Leu Leu Gly Lys Phe Glu Leu Thr Gly Ile 450 455 460 Pro Pro Ala Pro Arg Gly Val Pro Gln Ile Glu Val Thr Phe Asp Ile 465 470 475 480 Asp Ala Asn Gly Ile Leu Asn Val Ser Ala Val Asp Lys Ser Thr Gly 485 490 495 Lys Glu Asn Lys Ile Thr Ile Thr Asn Asp Lys Gly Arg Leu Ser Lys 500 505 510 Glu Asp Ile Glu Arg Met Val Gln Glu Ala Glu Lys Tyr Lys Ala Glu 515 520 525 Asp Glu Lys Gln Arg Asp Lys Val Ser Ser Lys Asn Ser Leu Glu Ser 530 535 540 Tyr Ala Phe Asn Met Lys Ala Thr Val Glu Asp Glu Lys Leu Gln Gly 545 550 555 560 Lys Ile Asn Asp Glu Asp Lys Gln Lys Ile Leu Asp Lys Cys Asn Glu 565 570 575 Ile Ile Asn Trp Leu Asp Lys Asn Gln Thr Ala Glu Lys Glu Glu Phe 580 585 590 Glu His Gln Gln Lys Glu Leu Glu Lys Val Cys Asn Pro Ile Ile Thr 595 600 605 Lys Leu Tyr Gln Ser Ala Gly Gly Met Pro Gly Gly Met Pro Gly Gly 610 615 620 Phe Pro Gly Gly Gly Ala Pro Pro Ser Gly Gly Ala Ser Ser Gly Pro 625 630 635 640 Thr Ile Glu Glu Val Asp 645 26472PRTHomo sapiens 26Met Thr Thr Cys Ser Arg Gln Phe Thr Ser Ser Ser Ser Met Lys Gly 1 5 10 15 Ser Cys Gly Ile Gly Gly Gly Ile Gly Gly Gly Ser Ser Arg Ile Ser 20 25 30 Ser Val Leu Ala Gly Gly Ser Cys Arg Ala Pro Ser Thr Tyr Gly Gly 35 40 45 Gly Leu Ser Val Ser Ser Ser Arg Phe Ser Ser Gly Gly Ala Cys Gly 50 55 60 Leu Gly Gly Gly Tyr Gly Gly Gly Phe Ser Ser Ser Ser Ser Ser Phe 65 70 75 80 Gly Ser Gly Phe Gly Gly Gly Tyr Gly Gly Gly Leu Gly Ala Gly Leu 85 90 95 Gly Gly Gly Phe Gly Gly Gly Phe Ala Gly Gly Asp Gly Leu Leu Val 100 105 110 Gly Ser Glu Lys Val Thr Met Gln Asn Leu Asn Asp Arg Leu Ala Ser 115 120 125 Tyr Leu Asp Lys Val Arg Ala Leu Glu Glu Ala Asn Ala Asp Leu Glu 130 135 140 Val Lys Ile Arg Asp Trp Tyr Gln Arg Gln Arg Pro Ala Glu Ile Lys 145 150 155 160 Asp Tyr Ser Pro Tyr Phe Lys Thr Ile Glu Asp Leu Arg Asn Lys Ile 165 170 175 Leu Thr Ala Thr Val Asp Asn Ala Asn Val Leu Leu Gln Ile Asp Asn 180 185 190 Ala Arg Leu Ala Ala Asp Asp Phe Arg Thr Lys Tyr Glu Thr Glu Leu 195 200 205 Asn Leu Arg Met Ser Val Glu Ala Asp Ile Asn Gly Leu Arg Arg Val 210 215 220 Leu Asp Glu Leu Thr Leu Ala Arg Ala Asp Leu Glu Met Gln Ile Glu 225 230 235 240 Ser Leu Lys Glu Glu Leu Ala Tyr Leu Lys Lys Asn His Glu Glu Glu 245 250 255 Met Asn Ala Leu Arg Gly Gln Val Gly Gly Asp Val Asn Val Glu Met 260 265 270 Asp Ala Ala Pro Gly Val Asp Leu Ser Arg Ile Leu Asn Glu Met Arg 275 280 285 Asp Gln Tyr Glu Lys Met Ala Glu Lys Asn Arg Lys Asp Ala Glu Glu 290 295 300 Trp Phe Phe Thr Lys Thr Glu Glu Leu Asn Arg Glu Val Ala Thr Asn 305 310 315 320 Ser Glu Leu Val Gln Ser Gly Lys Ser Glu Ile Ser Glu Leu Arg Arg 325 330 335 Thr Met Gln Asn Leu Glu Ile Glu Leu Gln Ser Gln Leu Ser Met Lys 340 345 350 Ala Ser Leu Glu Asn Ser Leu Glu Glu Thr Lys Gly Arg Tyr Cys Met 355 360 365 Gln Leu Ala Gln Ile Gln Glu Met Ile Gly Ser Val Glu Glu Gln Leu 370 375 380 Ala Gln Leu Arg Cys Glu Met Glu Gln Gln Asn Gln Glu Tyr Lys Ile 385 390 395 400 Leu Leu Asp Val Lys Thr Arg Leu Glu Gln Glu Ile Ala Thr Tyr Arg 405 410 415 Arg Leu Leu Glu Gly Glu Asp Ala His Leu Ser Ser Ser Gln Phe Ser 420 425 430 Ser Gly Ser Gln Ser Ser Arg Asp Val Thr Ser Ser Ser Arg Gln Ile 435 440 445 Arg Thr Lys Val Met Asp Val His Asp Gly Lys Val Val Ser Thr His 450 455 460 Glu Gln Val Leu Arg Thr Lys Asn 465 470 27156PRTHomo sapiens 27Met Gln Ile Phe Val Lys Thr Leu Thr Gly Lys Thr Ile Thr Leu Glu 1 5 10 15 Val Glu Pro Ser Asp Thr Ile Glu Asn Val Lys Ala Lys Ile Gln Asp 20 25 30 Lys Glu Gly Ile Pro Pro Asp Gln Gln Arg Leu Ile Phe Ala Gly Lys 35 40 45 Gln Leu Glu Asp Gly Arg Thr Leu Ser Asp Tyr Asn Ile Gln Lys Glu 50 55 60 Ser Thr Leu His Leu Val Leu Arg Leu Arg Gly Gly Ala Lys Lys Arg 65 70 75 80 Lys Lys Lys Ser Tyr Thr Thr Pro Lys Lys Asn Lys His Lys Arg Lys 85 90 95 Lys Val Lys Leu Ala Val Leu Lys Tyr Tyr Lys Val Asp Glu Asn Gly 100 105 110 Lys Ile Ser Arg Leu Arg Arg Glu Cys Pro Ser Asp Glu Cys Gly Ala 115 120 125 Gly Val Phe Met Ala Ser His Phe Asp Arg His Tyr Cys Gly Lys Cys 130 135 140 Cys Leu Thr Tyr Cys Phe Asn Lys Pro Glu Asp Lys 145 150 155 28631PRTHomo sapiens 28Met Glu Ser Tyr His Lys Pro Asp Gln Gln Lys Leu Gln Ala Leu Lys 1 5 10 15 Asp Thr Ala Asn Arg Leu Arg Ile Ser Ser Ile Gln Ala Thr Thr Ala 20 25 30 Ala Gly Ser Gly His Pro Thr Ser Cys Cys Ser Ala Ala Glu Ile Met 35 40 45 Ala Val Leu Phe Phe His Thr Met Arg Tyr Lys Ser Gln Asp Pro Arg 50 55 60 Asn Pro His Asn Asp Arg Phe Val Leu Ser Lys Gly His Ala Ala Pro 65 70 75 80 Ile Leu Tyr Ala Val Trp Ala Glu Ala Gly Phe Leu Ala Glu Ala Glu 85 90 95 Leu Leu Asn Leu Arg Lys Ile Ser Ser Asp Leu Asp Gly His Pro Val 100 105 110 Pro Lys Gln Ala Phe Thr Asp Val Ala Thr Gly Ser Leu Gly Gln Gly 115 120 125 Leu Gly Ala Ala Cys Gly Met Ala Tyr Thr Gly Lys Tyr Phe Asp Lys 130 135 140 Ala Ser Leu Pro Ser Ser Trp Asp Tyr Ser Tyr Arg Val Tyr Cys Leu 145 150 155 160 Leu Gly Asp Gly Glu Leu Ser Glu Gly Ser Val Trp Glu Ala Met Ala 165 170 175 Phe Ala Ser Ile Tyr Lys Leu Asp Asn Leu Val Ala Ile Leu Asp Ile 180 185 190 Asn Arg Leu Gly Gln Ser Asp Pro Ala Pro Leu Gln His Gln Met Asp 195 200 205 Ile Tyr Gln Lys Arg Cys Glu Ala Phe Gly Trp His Ala Ile Ile Val 210 215 220 Asp Gly His Ser Val Glu Glu Leu Cys Lys Ala Phe Gly Gln Ala Lys 225 230 235 240 His Gln Pro Thr Ala Ile Ile Ala Lys Thr Phe Lys Gly Arg Gly Ile 245 250 255 Thr Gly Val Glu Asp Lys Glu Ser Trp His Gly Lys Pro Leu Pro Lys 260 265 270 Asn Met Ala Glu Gln Ile Ile Gln Glu Ile Tyr Ser Gln Ile Gln Ser 275 280 285 Lys Lys Lys Ile Leu Ala Thr Pro Pro Gln Glu Asp Ala Pro Ser Val 290 295 300 Asp Ile Ala Asn Ile Arg Met Pro Ser Leu Pro Ser Tyr Lys Val Gly 305 310 315 320 Asp Lys Ile Ala Thr Arg Lys Ala Tyr Gly Gln Ala Leu Ala Lys Leu 325 330 335 Gly His Ala Ser Asp Arg Ile Ile Ala Leu Asp Gly Asp Thr Lys Asn 340 345 350 Ser Thr Phe Ser Glu Ile Phe Lys Lys Glu His Pro Asp Arg Phe Ile 355 360 365 Glu Cys Tyr Ile Ala Gly Gln Asn Met Val Ser Ile Ala Val Gly Cys 370 375 380 Ala Thr Arg Asn Arg Thr Val Pro Phe Cys Ser Thr Phe Ala Ala Phe 385 390 395 400 Phe Thr Arg Ala Phe Asp Gln Ile Arg Met Ala Ala Ile Ser Glu Ser 405 410 415 Asn Ile Asn Leu Cys Gly Ser His Cys Gly Val Ser Ile Gly Glu Asp 420 425 430 Gly Pro Ser Gln Met Ala Leu Glu Asp Leu Ala Met Phe Arg Ser Val 435 440 445 Pro Thr Ser Thr Val Phe Tyr Pro Ser Asp Gly Val Ala Thr Glu Lys 450 455 460 Ala Val Glu Leu Ala Ala Asn Thr Lys Gly Ile Cys Phe Ile Arg Thr 465 470 475 480 Ser Arg Pro Glu Asn Ala Ile Ile Tyr Asn Asn Asn Glu Asp Phe Gln 485 490 495 Val Gly Gln Ala Lys Val Val Leu Lys Ser Lys Asp Asp Gln Val Thr 500 505 510 Val Ile Gly Ala Gly Val Thr Leu His Glu Ala Leu Ala Ala Ala Glu 515 520 525 Leu Leu Lys Lys Glu Lys Ile Asn Ile Arg Val Leu Asp Pro Phe Thr 530 535 540 Ile Lys Pro Leu Asp Arg Lys Leu Ile Leu Asp Ser Ala Arg Ala Thr 545 550 555 560 Lys Gly Arg Ile Leu Thr Val Glu Asp His Tyr Tyr Glu Gly Gly Ile 565 570 575 Gly Glu Ala Val Ser Ser Ala Val Val Gly Glu Pro Gly Ile Thr Val 580 585 590 Thr His Leu Ala Val Asn Arg Val Pro Arg Ser Gly Lys Pro Ala Glu 595 600 605 Leu Leu Lys Met Phe Gly Ile Asp Arg Asp Ala Ile Ala Gln Ala Val 610 615 620 Arg Gly Leu Ile Thr Lys Ala 625 630 29135PRTHomo sapiens 29Met Ala Cys Gly Leu Val Ala Ser Asn Leu Asn Leu Lys Pro Gly Glu 1 5 10 15 Cys Leu Arg Val Arg Gly Glu Val Ala Pro Asp Ala Lys Ser Phe Val 20 25 30 Leu Asn Leu Gly Lys Asp Ser Asn Asn Leu Cys Leu His Phe Asn Pro 35 40 45 Arg Phe Asn Ala His Gly Asp Ala Asn Thr Ile Val Cys Asn Ser Lys 50 55 60 Asp Gly Gly Ala Trp Gly Thr Glu Gln Arg Glu Ala Val Phe Pro Phe 65 70 75 80 Gln Pro Gly Ser Val Ala Glu Val Cys Ile Thr Phe Asp Gln Ala Asn 85 90 95 Leu Thr Val Lys Leu Pro Asp Gly Tyr Glu Phe Lys Phe Pro Asn Arg 100 105 110 Leu Asn Leu Glu Ala Ile Asn Tyr Met Ala Ala Asp Gly Asp Phe Lys 115 120 125 Ile Lys Cys Val Ala Phe Asp 130 135 30511PRTHomo sapiens 30Met Ser Lys Pro His Ser Glu Ala Gly Thr Ala Phe Ile Gln Thr Gln 1 5 10

15 Gln Leu His Ala Ala Met Ala Asp Thr Phe Leu Glu His Met Cys Arg 20 25 30 Leu Asp Ile Asp Ser Pro Pro Ile Thr Ala Arg Asn Thr Gly Ile Ile 35 40 45 Cys Thr Ile Gly Pro Ala Ser Arg Ser Val Glu Thr Leu Lys Glu Met 50 55 60 Ile Lys Ser Gly Met Asn Val Ala Arg Leu Asn Phe Ser His Gly Thr 65 70 75 80 His Glu Tyr His Ala Glu Thr Ile Lys Asn Val Arg Thr Ala Thr Glu 85 90 95 Ser Phe Ala Ser Asp Pro Ile Leu Tyr Arg Ser Gly Thr Ala Glu Val 100 105 110 Glu Leu Lys Lys Gly Ala Thr Leu Lys Ile Thr Leu Asp Asn Ala Tyr 115 120 125 Met Glu Lys Cys Asp Glu Asn Ile Leu Trp Leu Asp Tyr Lys Asn Ile 130 135 140 Cys Lys Val Val Glu Val Gly Ser Lys Ile Tyr Val Asp Asp Gly Leu 145 150 155 160 Ile Ser Leu Gln Val Lys Gln Lys Gly Ala Asp Phe Leu Val Thr Glu 165 170 175 Val Glu Asn Gly Gly Ser Leu Gly Ser Lys Lys Gly Val Asn Leu Pro 180 185 190 Gly Ala Ala Val Asp Leu Pro Ala Val Ser Glu Lys Asp Ile Gln Asp 195 200 205 Leu Lys Phe Gly Val Glu Gln Asp Val Asp Met Val Phe Ala Ser Phe 210 215 220 Ile Arg Lys Ala Ser Asp Val His Glu Val Arg Lys Val Leu Gly Glu 225 230 235 240 Lys Gly Lys Asn Ile Lys Ile Ile Ser Lys Ile Glu Asn His Glu Gly 245 250 255 Val Arg Arg Phe Asp Glu Ile Leu Glu Ala Ser Asp Gly Ile Met Val 260 265 270 Ala Arg Gly Asp Leu Gly Ile Glu Ile Pro Ala Glu Lys Val Phe Leu 275 280 285 Ala Gln Lys Met Met Ile Gly Arg Cys Asn Arg Ala Gly Lys Pro Val 290 295 300 Ile Cys Ala Thr Gln Met Leu Glu Ser Met Ile Lys Lys Pro Arg Pro 305 310 315 320 Thr Arg Ala Glu Gly Ser Asp Val Ala Asn Ala Val Leu Asp Gly Ala 325 330 335 Asp Cys Ile Met Leu Ser Gly Glu Thr Ala Lys Gly Asp Tyr Pro Leu 340 345 350 Glu Ala Val Arg Met Gln His Leu Ile Ala Arg Glu Ala Glu Ala Ala 355 360 365 Met Phe His Arg Lys Leu Phe Glu Glu Leu Val Arg Ala Ser Ser His 370 375 380 Ser Thr Asp Leu Met Glu Ala Met Ala Met Gly Ser Val Glu Ala Ser 385 390 395 400 Tyr Lys Cys Leu Ala Ala Ala Leu Ile Val Leu Thr Glu Ser Gly Arg 405 410 415 Ser Ala His Gln Val Ala Arg Tyr Arg Pro Arg Ala Pro Ile Ile Ala 420 425 430 Val Thr Arg Asn Pro Gln Thr Ala Arg Gln Ala His Leu Tyr Arg Gly 435 440 445 Ile Phe Pro Val Leu Cys Lys Asp Pro Val Gln Glu Ala Trp Ala Glu 450 455 460 Asp Val Asp Leu Arg Val Asn Phe Ala Met Asn Val Gly Lys Ala Arg 465 470 475 480 Gly Phe Phe Lys Lys Gly Asp Val Val Ile Val Leu Thr Gly Trp Arg 485 490 495 Pro Gly Ser Gly Phe Thr Asn Thr Met Arg Val Val Pro Val Pro 500 505 510 31124PRTHomo sapiens 31Met Ser Met Lys Glu Val Asp Glu Gln Met Leu Asn Val Gln Asn Lys 1 5 10 15 Asn Ser Ser Tyr Phe Val Glu Trp Ile Pro Asn Asn Val Lys Thr Ala 20 25 30 Val Cys Asp Ile Pro Pro Arg Gly Leu Lys Met Ala Val Thr Phe Ile 35 40 45 Gly Asn Ser Thr Ala Ile Gln Glu Leu Phe Lys Arg Ile Ser Glu Gln 50 55 60 Phe Thr Ala Met Phe Arg Arg Lys Ala Phe Leu His Trp Tyr Thr Gly 65 70 75 80 Glu Gly Met Asp Glu Met Glu Phe Thr Glu Ala Glu Ser Asn Met Asn 85 90 95 Asp Leu Val Ser Glu Tyr Gln Gln Tyr Gln Asp Ala Thr Ala Glu Glu 100 105 110 Glu Glu Asp Phe Gly Glu Glu Ala Glu Glu Glu Ala 115 120 32294PRTHomo sapiens 32Met Glu Asp Ser Met Asp Met Asp Met Ser Pro Leu Arg Pro Gln Asn 1 5 10 15 Tyr Leu Phe Gly Cys Glu Leu Lys Ala Asp Lys Asp Tyr His Phe Lys 20 25 30 Val Asp Asn Asp Glu Asn Glu His Gln Leu Ser Leu Arg Thr Val Ser 35 40 45 Leu Gly Ala Gly Ala Lys Asp Glu Leu His Ile Val Glu Ala Glu Ala 50 55 60 Met Asn Tyr Glu Gly Ser Pro Ile Lys Val Thr Leu Ala Thr Leu Lys 65 70 75 80 Met Ser Val Gln Pro Thr Val Ser Leu Gly Gly Phe Glu Ile Thr Pro 85 90 95 Pro Val Val Leu Arg Leu Lys Cys Gly Ser Gly Pro Val His Ile Ser 100 105 110 Gly Gln His Leu Val Ala Val Glu Glu Asp Ala Glu Ser Glu Asp Glu 115 120 125 Glu Glu Glu Asp Val Lys Leu Leu Ser Ile Ser Gly Lys Arg Ser Ala 130 135 140 Pro Gly Gly Gly Ser Lys Val Pro Gln Lys Lys Val Lys Leu Ala Ala 145 150 155 160 Asp Glu Asp Asp Asp Asp Asp Asp Glu Glu Asp Asp Asp Glu Asp Asp 165 170 175 Asp Asp Asp Asp Phe Asp Asp Glu Glu Ala Glu Glu Lys Ala Pro Val 180 185 190 Lys Lys Ser Ile Arg Asp Thr Pro Ala Lys Asn Ala Gln Lys Ser Asn 195 200 205 Gln Asn Gly Lys Asp Ser Lys Pro Ser Ser Thr Pro Arg Ser Lys Gly 210 215 220 Gln Glu Ser Phe Lys Lys Gln Glu Lys Thr Pro Lys Thr Pro Lys Gly 225 230 235 240 Pro Ser Ser Val Glu Asp Ile Lys Ala Lys Met Gln Ala Ser Ile Glu 245 250 255 Lys Gly Gly Ser Leu Pro Lys Val Glu Ala Lys Phe Ile Asn Tyr Val 260 265 270 Lys Asn Cys Phe Arg Met Thr Asp Gln Glu Ala Ile Gln Asp Leu Trp 275 280 285 Gln Trp Arg Lys Ser Leu 290 33152PRTHomo sapiens 33Met Ala Asn Leu Glu Arg Thr Phe Ile Ala Ile Lys Pro Asp Gly Val 1 5 10 15 Gln Arg Gly Leu Val Gly Glu Ile Ile Lys Arg Phe Glu Gln Lys Gly 20 25 30 Phe Arg Leu Val Ala Met Lys Phe Leu Arg Ala Ser Glu Glu His Leu 35 40 45 Lys Gln His Tyr Ile Asp Leu Lys Asp Arg Pro Phe Phe Pro Gly Leu 50 55 60 Val Lys Tyr Met Asn Ser Gly Pro Val Val Ala Met Val Trp Glu Gly 65 70 75 80 Leu Asn Val Val Lys Thr Gly Arg Val Met Leu Gly Glu Thr Asn Pro 85 90 95 Ala Asp Ser Lys Pro Gly Thr Ile Arg Gly Asp Phe Cys Ile Gln Val 100 105 110 Gly Arg Asn Ile Ile His Gly Ser Asp Ser Val Lys Ser Ala Glu Lys 115 120 125 Glu Ile Ser Leu Trp Phe Lys Pro Glu Glu Leu Val Asp Tyr Lys Ser 130 135 140 Cys Ala His Asp Trp Val Tyr Glu 145 150 341170PRTHomo sapiens 34Met Gly Leu Ala Trp Gly Leu Gly Val Leu Phe Leu Met His Val Cys 1 5 10 15 Gly Thr Asn Arg Ile Pro Glu Ser Gly Gly Asp Asn Ser Val Phe Asp 20 25 30 Ile Phe Glu Leu Thr Gly Ala Ala Arg Lys Gly Ser Gly Arg Arg Leu 35 40 45 Val Lys Gly Pro Asp Pro Ser Ser Pro Ala Phe Arg Ile Glu Asp Ala 50 55 60 Asn Leu Ile Pro Pro Val Pro Asp Asp Lys Phe Gln Asp Leu Val Asp 65 70 75 80 Ala Val Arg Ala Glu Lys Gly Phe Leu Leu Leu Ala Ser Leu Arg Gln 85 90 95 Met Lys Lys Thr Arg Gly Thr Leu Leu Ala Leu Glu Arg Lys Asp His 100 105 110 Ser Gly Gln Val Phe Ser Val Val Ser Asn Gly Lys Ala Gly Thr Leu 115 120 125 Asp Leu Ser Leu Thr Val Gln Gly Lys Gln His Val Val Ser Val Glu 130 135 140 Glu Ala Leu Leu Ala Thr Gly Gln Trp Lys Ser Ile Thr Leu Phe Val 145 150 155 160 Gln Glu Asp Arg Ala Gln Leu Tyr Ile Asp Cys Glu Lys Met Glu Asn 165 170 175 Ala Glu Leu Asp Val Pro Ile Gln Ser Val Phe Thr Arg Asp Leu Ala 180 185 190 Ser Ile Ala Arg Leu Arg Ile Ala Lys Gly Gly Val Asn Asp Asn Phe 195 200 205 Gln Gly Val Leu Gln Asn Val Arg Phe Val Phe Gly Thr Thr Pro Glu 210 215 220 Asp Ile Leu Arg Asn Lys Gly Cys Ser Ser Ser Thr Ser Val Leu Leu 225 230 235 240 Thr Leu Asp Asn Asn Val Val Asn Gly Ser Ser Pro Ala Ile Arg Thr 245 250 255 Asn Tyr Ile Gly His Lys Thr Lys Asp Leu Gln Ala Ile Cys Gly Ile 260 265 270 Ser Cys Asp Glu Leu Ser Ser Met Val Leu Glu Leu Arg Gly Leu Arg 275 280 285 Thr Ile Val Thr Thr Leu Gln Asp Ser Ile Arg Lys Val Thr Glu Glu 290 295 300 Asn Lys Glu Leu Ala Asn Glu Leu Arg Arg Pro Pro Leu Cys Tyr His 305 310 315 320 Asn Gly Val Gln Tyr Arg Asn Asn Glu Glu Trp Thr Val Asp Ser Cys 325 330 335 Thr Glu Cys His Cys Gln Asn Ser Val Thr Ile Cys Lys Lys Val Ser 340 345 350 Cys Pro Ile Met Pro Cys Ser Asn Ala Thr Val Pro Asp Gly Glu Cys 355 360 365 Cys Pro Arg Cys Trp Pro Ser Asp Ser Ala Asp Asp Gly Trp Ser Pro 370 375 380 Trp Ser Glu Trp Thr Ser Cys Ser Thr Ser Cys Gly Asn Gly Ile Gln 385 390 395 400 Gln Arg Gly Arg Ser Cys Asp Ser Leu Asn Asn Arg Cys Glu Gly Ser 405 410 415 Ser Val Gln Thr Arg Thr Cys His Ile Gln Glu Cys Asp Lys Arg Phe 420 425 430 Lys Gln Asp Gly Gly Trp Ser His Trp Ser Pro Trp Ser Ser Cys Ser 435 440 445 Val Thr Cys Gly Asp Gly Val Ile Thr Arg Ile Arg Leu Cys Asn Ser 450 455 460 Pro Ser Pro Gln Met Asn Gly Lys Pro Cys Glu Gly Glu Ala Arg Glu 465 470 475 480 Thr Lys Ala Cys Lys Lys Asp Ala Cys Pro Ile Asn Gly Gly Trp Gly 485 490 495 Pro Trp Ser Pro Trp Asp Ile Cys Ser Val Thr Cys Gly Gly Gly Val 500 505 510 Gln Lys Arg Ser Arg Leu Cys Asn Asn Pro Thr Pro Gln Phe Gly Gly 515 520 525 Lys Asp Cys Val Gly Asp Val Thr Glu Asn Gln Ile Cys Asn Lys Gln 530 535 540 Asp Cys Pro Ile Asp Gly Cys Leu Ser Asn Pro Cys Phe Ala Gly Val 545 550 555 560 Lys Cys Thr Ser Tyr Pro Asp Gly Ser Trp Lys Cys Gly Ala Cys Pro 565 570 575 Pro Gly Tyr Ser Gly Asn Gly Ile Gln Cys Thr Asp Val Asp Glu Cys 580 585 590 Lys Glu Val Pro Asp Ala Cys Phe Asn His Asn Gly Glu His Arg Cys 595 600 605 Glu Asn Thr Asp Pro Gly Tyr Asn Cys Leu Pro Cys Pro Pro Arg Phe 610 615 620 Thr Gly Ser Gln Pro Phe Gly Gln Gly Val Glu His Ala Thr Ala Asn 625 630 635 640 Lys Gln Val Cys Lys Pro Arg Asn Pro Cys Thr Asp Gly Thr His Asp 645 650 655 Cys Asn Lys Asn Ala Lys Cys Asn Tyr Leu Gly His Tyr Ser Asp Pro 660 665 670 Met Tyr Arg Cys Glu Cys Lys Pro Gly Tyr Ala Gly Asn Gly Ile Ile 675 680 685 Cys Gly Glu Asp Thr Asp Leu Asp Gly Trp Pro Asn Glu Asn Leu Val 690 695 700 Cys Val Ala Asn Ala Thr Tyr His Cys Lys Lys Asp Asn Cys Pro Asn 705 710 715 720 Leu Pro Asn Ser Gly Gln Glu Asp Tyr Asp Lys Asp Gly Ile Gly Asp 725 730 735 Ala Cys Asp Asp Asp Asp Asp Asn Asp Lys Ile Pro Asp Asp Arg Asp 740 745 750 Asn Cys Pro Phe His Tyr Asn Pro Ala Gln Tyr Asp Tyr Asp Arg Asp 755 760 765 Asp Val Gly Asp Arg Cys Asp Asn Cys Pro Tyr Asn His Asn Pro Asp 770 775 780 Gln Ala Asp Thr Asp Asn Asn Gly Glu Gly Asp Ala Cys Ala Ala Asp 785 790 795 800 Ile Asp Gly Asp Gly Ile Leu Asn Glu Arg Asp Asn Cys Gln Tyr Val 805 810 815 Tyr Asn Val Asp Gln Arg Asp Thr Asp Met Asp Gly Val Gly Asp Gln 820 825 830 Cys Asp Asn Cys Pro Leu Glu His Asn Pro Asp Gln Leu Asp Ser Asp 835 840 845 Ser Asp Arg Ile Gly Asp Thr Cys Asp Asn Asn Gln Asp Ile Asp Glu 850 855 860 Asp Gly His Gln Asn Asn Leu Asp Asn Cys Pro Tyr Val Pro Asn Ala 865 870 875 880 Asn Gln Ala Asp His Asp Lys Asp Gly Lys Gly Asp Ala Cys Asp His 885 890 895 Asp Asp Asp Asn Asp Gly Ile Pro Asp Asp Lys Asp Asn Cys Arg Leu 900 905 910 Val Pro Asn Pro Asp Gln Lys Asp Ser Asp Gly Asp Gly Arg Gly Asp 915 920 925 Ala Cys Lys Asp Asp Phe Asp His Asp Ser Val Pro Asp Ile Asp Asp 930 935 940 Ile Cys Pro Glu Asn Val Asp Ile Ser Glu Thr Asp Phe Arg Arg Phe 945 950 955 960 Gln Met Ile Pro Leu Asp Pro Lys Gly Thr Ser Gln Asn Asp Pro Asn 965 970 975 Trp Val Val Arg His Gln Gly Lys Glu Leu Val Gln Thr Val Asn Cys 980 985 990 Asp Pro Gly Leu Ala Val Gly Tyr Asp Glu Phe Asn Ala Val Asp Phe 995 1000 1005 Ser Gly Thr Phe Phe Ile Asn Thr Glu Arg Asp Asp Asp Tyr Ala 1010 1015 1020 Gly Phe Val Phe Gly Tyr Gln Ser Ser Ser Arg Phe Tyr Val Val 1025 1030 1035 Met Trp Lys Gln Val Thr Gln Ser Tyr Trp Asp Thr Asn Pro Thr 1040 1045 1050 Arg Ala Gln Gly Tyr Ser Gly Leu Ser Val Lys Val Val Asn Ser 1055 1060 1065 Thr Thr Gly Pro Gly Glu His Leu Arg Asn Ala Leu Trp His Thr 1070 1075 1080 Gly Asn Thr Pro Gly Gln Val Arg Thr Leu Trp His Asp Pro Arg 1085 1090 1095 His Ile Gly Trp Lys Asp Phe Thr Ala Tyr Arg Trp Arg Leu Ser 1100 1105 1110 His Arg Pro Lys Thr Gly Phe Ile Arg Val Val Met Tyr Glu Gly 1115 1120 1125 Lys Lys Ile Met Ala Asp Ser Gly Pro Ile Tyr Asp Lys Thr Tyr 1130 1135 1140 Ala Gly Gly Arg Leu Gly Leu Phe Val Phe Ser Gln Glu Met Val 1145 1150 1155 Phe Phe Ser Asp Leu Lys Tyr Glu Cys Arg Asp Pro 1160 1165 1170 35332PRTHomo sapiens 35Met Ala Thr Leu Lys Asp Gln Leu Ile Tyr Asn Leu Leu Lys Glu Glu 1 5 10 15 Gln Thr Pro Gln Asn Lys Ile Thr Val Val Gly Val Gly Ala Val Gly 20 25 30 Met Ala Cys Ala Ile Ser Ile Leu Met Lys Asp Leu Ala Asp Glu Leu 35 40 45

Ala Leu Val Asp Val Ile Glu Asp Lys Leu Lys Gly Glu Met Met Asp 50 55 60 Leu Gln His Gly Ser Leu Phe Leu Arg Thr Pro Lys Ile Val Ser Gly 65 70 75 80 Lys Asp Tyr Asn Val Thr Ala Asn Ser Lys Leu Val Ile Ile Thr Ala 85 90 95 Gly Ala Arg Gln Gln Glu Gly Glu Ser Arg Leu Asn Leu Val Gln Arg 100 105 110 Asn Val Asn Ile Phe Lys Phe Ile Ile Pro Asn Val Val Lys Tyr Ser 115 120 125 Pro Asn Cys Lys Leu Leu Ile Val Ser Asn Pro Val Asp Ile Leu Thr 130 135 140 Tyr Val Ala Trp Lys Ile Ser Gly Phe Pro Lys Asn Arg Val Ile Gly 145 150 155 160 Ser Gly Cys Asn Leu Asp Ser Ala Arg Phe Arg Tyr Leu Met Gly Glu 165 170 175 Arg Leu Gly Val His Pro Leu Ser Cys His Gly Trp Val Leu Gly Glu 180 185 190 His Gly Asp Ser Ser Val Pro Val Trp Ser Gly Met Asn Val Ala Gly 195 200 205 Val Ser Leu Lys Thr Leu His Pro Asp Leu Gly Thr Asp Lys Asp Lys 210 215 220 Glu Gln Trp Lys Glu Val His Lys Gln Val Val Glu Ser Ala Tyr Glu 225 230 235 240 Val Ile Lys Leu Lys Gly Tyr Thr Ser Trp Ala Ile Gly Leu Ser Val 245 250 255 Ala Asp Leu Ala Glu Ser Ile Met Lys Asn Leu Arg Arg Val His Pro 260 265 270 Val Ser Thr Met Ile Lys Gly Leu Tyr Gly Ile Lys Asp Asp Val Phe 275 280 285 Leu Ser Val Pro Cys Ile Leu Gly Gln Asn Gly Ile Ser Asp Leu Val 290 295 300 Lys Val Thr Leu Thr Ser Glu Glu Glu Ala Arg Leu Lys Lys Ser Ala 305 310 315 320 Asp Thr Leu Trp Gly Ile Gln Lys Glu Leu Gln Phe 325 330 36590PRTHomo sapiens 36Met Ser Arg Gln Ser Ser Val Ser Phe Arg Ser Gly Gly Ser Arg Ser 1 5 10 15 Phe Ser Thr Ala Ser Ala Ile Thr Pro Ser Val Ser Arg Thr Ser Phe 20 25 30 Thr Ser Val Ser Arg Ser Gly Gly Gly Gly Gly Gly Gly Phe Gly Arg 35 40 45 Val Ser Leu Ala Gly Ala Cys Gly Val Gly Gly Tyr Gly Ser Arg Ser 50 55 60 Leu Tyr Asn Leu Gly Gly Ser Lys Arg Ile Ser Ile Ser Thr Ser Gly 65 70 75 80 Gly Ser Phe Arg Asn Arg Phe Gly Ala Gly Ala Gly Gly Gly Tyr Gly 85 90 95 Phe Gly Gly Gly Ala Gly Ser Gly Phe Gly Phe Gly Gly Gly Ala Gly 100 105 110 Gly Gly Phe Gly Leu Gly Gly Gly Ala Gly Phe Gly Gly Gly Phe Gly 115 120 125 Gly Pro Gly Phe Pro Val Cys Pro Pro Gly Gly Ile Gln Glu Val Thr 130 135 140 Val Asn Gln Ser Leu Leu Thr Pro Leu Asn Leu Gln Ile Asp Pro Ser 145 150 155 160 Ile Gln Arg Val Arg Thr Glu Glu Arg Glu Gln Ile Lys Thr Leu Asn 165 170 175 Asn Lys Phe Ala Ser Phe Ile Asp Lys Val Arg Phe Leu Glu Gln Gln 180 185 190 Asn Lys Val Leu Asp Thr Lys Trp Thr Leu Leu Gln Glu Gln Gly Thr 195 200 205 Lys Thr Val Arg Gln Asn Leu Glu Pro Leu Phe Glu Gln Tyr Ile Asn 210 215 220 Asn Leu Arg Arg Gln Leu Asp Ser Ile Val Gly Glu Arg Gly Arg Leu 225 230 235 240 Asp Ser Glu Leu Arg Asn Met Gln Asp Leu Val Glu Asp Phe Lys Asn 245 250 255 Lys Tyr Glu Asp Glu Ile Asn Lys Arg Thr Thr Ala Glu Asn Glu Phe 260 265 270 Val Met Leu Lys Lys Asp Val Asp Ala Ala Tyr Met Asn Lys Val Glu 275 280 285 Leu Glu Ala Lys Val Asp Ala Leu Met Asp Glu Ile Asn Phe Met Lys 290 295 300 Met Phe Phe Asp Ala Glu Leu Ser Gln Met Gln Thr His Val Ser Asp 305 310 315 320 Thr Ser Val Val Leu Ser Met Asp Asn Asn Arg Asn Leu Asp Leu Asp 325 330 335 Ser Ile Ile Ala Glu Val Lys Ala Gln Tyr Glu Glu Ile Ala Asn Arg 340 345 350 Ser Arg Thr Glu Ala Glu Ser Trp Tyr Gln Thr Lys Tyr Glu Glu Leu 355 360 365 Gln Gln Thr Ala Gly Arg His Gly Asp Asp Leu Arg Asn Thr Lys His 370 375 380 Glu Ile Ser Glu Met Asn Arg Met Ile Gln Arg Leu Arg Ala Glu Ile 385 390 395 400 Asp Asn Val Lys Lys Gln Cys Ala Asn Leu Gln Asn Ala Ile Ala Asp 405 410 415 Ala Glu Gln Arg Gly Glu Leu Ala Leu Lys Asp Ala Arg Asn Lys Leu 420 425 430 Ala Glu Leu Glu Glu Ala Leu Gln Lys Ala Lys Gln Asp Met Ala Arg 435 440 445 Leu Leu Arg Glu Tyr Gln Glu Leu Met Asn Thr Lys Leu Ala Leu Asp 450 455 460 Val Glu Ile Ala Thr Tyr Arg Lys Leu Leu Glu Gly Glu Glu Cys Arg 465 470 475 480 Leu Ser Gly Glu Gly Val Gly Pro Val Asn Ile Ser Val Val Thr Ser 485 490 495 Ser Val Ser Ser Gly Tyr Gly Ser Gly Ser Gly Tyr Gly Gly Gly Leu 500 505 510 Gly Gly Gly Leu Gly Gly Gly Leu Gly Gly Gly Leu Ala Gly Gly Ser 515 520 525 Ser Gly Ser Tyr Tyr Ser Ser Ser Ser Gly Gly Val Gly Leu Gly Gly 530 535 540 Gly Leu Ser Val Gly Gly Ser Gly Phe Ser Ala Ser Ser Gly Arg Gly 545 550 555 560 Leu Gly Val Gly Phe Gly Ser Gly Gly Gly Ser Ser Ser Ser Val Lys 565 570 575 Phe Val Ser Thr Thr Ser Ser Ser Arg Lys Ser Phe Lys Ser 580 585 590 37654PRTHomo sapiens 37Met Lys Leu Ser Leu Val Ala Ala Met Leu Leu Leu Leu Ser Ala Ala 1 5 10 15 Arg Ala Glu Glu Glu Asp Lys Lys Glu Asp Val Gly Thr Val Val Gly 20 25 30 Ile Asp Leu Gly Thr Thr Tyr Ser Cys Val Gly Val Phe Lys Asn Gly 35 40 45 Arg Val Glu Ile Ile Ala Asn Asp Gln Gly Asn Arg Ile Thr Pro Ser 50 55 60 Tyr Val Ala Phe Thr Pro Glu Gly Glu Arg Leu Ile Gly Asp Ala Ala 65 70 75 80 Lys Asn Gln Leu Thr Ser Asn Pro Glu Asn Thr Val Phe Asp Ala Lys 85 90 95 Arg Leu Ile Gly Arg Thr Trp Asn Asp Pro Ser Val Gln Gln Asp Ile 100 105 110 Lys Phe Leu Pro Phe Lys Val Val Glu Lys Lys Thr Lys Pro Tyr Ile 115 120 125 Gln Val Asp Ile Gly Gly Gly Gln Thr Lys Thr Phe Ala Pro Glu Glu 130 135 140 Ile Ser Ala Met Val Leu Thr Lys Met Lys Glu Thr Ala Glu Ala Tyr 145 150 155 160 Leu Gly Lys Lys Val Thr His Ala Val Val Thr Val Pro Ala Tyr Phe 165 170 175 Asn Asp Ala Gln Arg Gln Ala Thr Lys Asp Ala Gly Thr Ile Ala Gly 180 185 190 Leu Asn Val Met Arg Ile Ile Asn Glu Pro Thr Ala Ala Ala Ile Ala 195 200 205 Tyr Gly Leu Asp Lys Arg Glu Gly Glu Lys Asn Ile Leu Val Phe Asp 210 215 220 Leu Gly Gly Gly Thr Phe Asp Val Ser Leu Leu Thr Ile Asp Asn Gly 225 230 235 240 Val Phe Glu Val Val Ala Thr Asn Gly Asp Thr His Leu Gly Gly Glu 245 250 255 Asp Phe Asp Gln Arg Val Met Glu His Phe Ile Lys Leu Tyr Lys Lys 260 265 270 Lys Thr Gly Lys Asp Val Arg Lys Asp Asn Arg Ala Val Gln Lys Leu 275 280 285 Arg Arg Glu Val Glu Lys Ala Lys Arg Ala Leu Ser Ser Gln His Gln 290 295 300 Ala Arg Ile Glu Ile Glu Ser Phe Tyr Glu Gly Glu Asp Phe Ser Glu 305 310 315 320 Thr Leu Thr Arg Ala Lys Phe Glu Glu Leu Asn Met Asp Leu Phe Arg 325 330 335 Ser Thr Met Lys Pro Val Gln Lys Val Leu Glu Asp Ser Asp Leu Lys 340 345 350 Lys Ser Asp Ile Asp Glu Ile Val Leu Val Gly Gly Ser Thr Arg Ile 355 360 365 Pro Lys Ile Gln Gln Leu Val Lys Glu Phe Phe Asn Gly Lys Glu Pro 370 375 380 Ser Arg Gly Ile Asn Pro Asp Glu Ala Val Ala Tyr Gly Ala Ala Val 385 390 395 400 Gln Ala Gly Val Leu Ser Gly Asp Gln Asp Thr Gly Asp Leu Val Leu 405 410 415 Leu Asp Val Cys Pro Leu Thr Leu Gly Ile Glu Thr Val Gly Gly Val 420 425 430 Met Thr Lys Leu Ile Pro Arg Asn Thr Val Val Pro Thr Lys Lys Ser 435 440 445 Gln Ile Phe Ser Thr Ala Ser Asp Asn Gln Pro Thr Val Thr Ile Lys 450 455 460 Val Tyr Glu Gly Glu Arg Pro Leu Thr Lys Asp Asn His Leu Leu Gly 465 470 475 480 Thr Phe Asp Leu Thr Gly Ile Pro Pro Ala Pro Arg Gly Val Pro Gln 485 490 495 Ile Glu Val Thr Phe Glu Ile Asp Val Asn Gly Ile Leu Arg Val Thr 500 505 510 Ala Glu Asp Lys Gly Thr Gly Asn Lys Asn Lys Ile Thr Ile Thr Asn 515 520 525 Asp Gln Asn Arg Leu Thr Pro Glu Glu Ile Glu Arg Met Val Asn Asp 530 535 540 Ala Glu Lys Phe Ala Glu Glu Asp Lys Lys Leu Lys Glu Arg Ile Asp 545 550 555 560 Thr Arg Asn Glu Leu Glu Ser Tyr Ala Tyr Ser Leu Lys Asn Gln Ile 565 570 575 Gly Asp Lys Glu Lys Leu Gly Gly Lys Leu Ser Ser Glu Asp Lys Glu 580 585 590 Thr Met Glu Lys Ala Val Glu Glu Lys Ile Glu Trp Leu Glu Ser His 595 600 605 Gln Asp Ala Asp Ile Glu Asp Phe Lys Ala Lys Lys Lys Glu Leu Glu 610 615 620 Glu Ile Val Gln Pro Ile Ile Ser Lys Leu Tyr Gly Ser Ala Gly Pro 625 630 635 640 Pro Pro Thr Gly Glu Glu Asp Thr Ala Glu Lys Asp Glu Leu 645 650 3844PRTHomo sapiens 38Met Ala Asp Lys Pro Asp Met Gly Glu Ile Ala Ser Phe Asp Lys Ala 1 5 10 15 Lys Leu Lys Lys Thr Glu Thr Gln Glu Lys Asn Thr Leu Pro Thr Lys 20 25 30 Glu Thr Ile Glu Gln Glu Lys Arg Ser Glu Ile Ser 35 40 391111PRTHomo sapiens 39Met Pro Ala Leu Trp Leu Gly Cys Cys Leu Cys Phe Ser Leu Leu Leu 1 5 10 15 Pro Ala Ala Arg Ala Thr Ser Arg Arg Glu Val Cys Asp Cys Asn Gly 20 25 30 Lys Ser Arg Gln Cys Ile Phe Asp Arg Glu Leu His Arg Gln Thr Gly 35 40 45 Asn Gly Phe Arg Cys Leu Asn Cys Asn Asp Asn Thr Asp Gly Ile His 50 55 60 Cys Glu Lys Cys Lys Asn Gly Phe Tyr Arg His Arg Glu Arg Asp Arg 65 70 75 80 Cys Leu Pro Cys Asn Cys Asn Ser Lys Gly Ser Leu Ser Ala Arg Cys 85 90 95 Asp Asn Ser Gly Arg Cys Ser Cys Lys Pro Gly Val Thr Gly Ala Arg 100 105 110 Cys Asp Arg Cys Leu Pro Gly Phe His Met Leu Met Asp Ala Gly Cys 115 120 125 Thr Gln Asp Gln Arg Leu Leu Asp Ser Lys Cys Asp Cys Asp Pro Ala 130 135 140 Gly Ile Ala Gly Pro Cys Asp Ala Gly Arg Cys Val Cys Lys Pro Ala 145 150 155 160 Val Thr Gly Glu Arg Cys Asp Arg Cys Arg Ser Gly Tyr Tyr Asn Leu 165 170 175 Asp Gly Gly Asn Pro Glu Gly Cys Thr Gln Cys Phe Cys Tyr Gly His 180 185 190 Ser Ala Ser Cys Arg Ser Ser Ala Glu Tyr Ser Val His Lys Ile Thr 195 200 205 Ser Thr Phe His Gln Asp Val Asp Gly Trp Lys Ala Val Gln Arg Asn 210 215 220 Gly Ser Pro Ala Lys Leu Gln Trp Ser Gln Arg His Gln Asp Val Phe 225 230 235 240 Ser Ser Ala Gln Arg Leu Asp Pro Val Tyr Phe Val Ala Pro Ala Lys 245 250 255 Phe Leu Gly Asn Gln Gln Val Ser Tyr Gly Gln Ser Leu Ser Phe Asp 260 265 270 Tyr Arg Val Asp Arg Gly Gly Arg His Pro Ser Ala His Asp Val Ile 275 280 285 Leu Glu Gly Ala Gly Leu Arg Ile Thr Ala Pro Leu Met Pro Leu Gly 290 295 300 Lys Thr Leu Pro Cys Gly Leu Thr Lys Thr Tyr Thr Phe Arg Leu Asn 305 310 315 320 Glu His Pro Ser Asn Asn Trp Ser Pro Gln Leu Ser Tyr Phe Glu Tyr 325 330 335 Arg Arg Leu Leu Arg Asn Leu Thr Ala Leu Arg Ile Arg Ala Thr Tyr 340 345 350 Gly Glu Tyr Ser Thr Gly Tyr Ile Asp Asn Val Thr Leu Ile Ser Ala 355 360 365 Arg Pro Val Ser Gly Ala Pro Ala Pro Trp Val Glu Gln Cys Ile Cys 370 375 380 Pro Val Gly Tyr Lys Gly Gln Phe Cys Gln Asp Cys Ala Ser Gly Tyr 385 390 395 400 Lys Arg Asp Ser Ala Arg Leu Gly Pro Phe Gly Thr Cys Ile Pro Cys 405 410 415 Asn Cys Gln Gly Gly Gly Ala Cys Asp Pro Asp Thr Gly Asp Cys Tyr 420 425 430 Ser Gly Asp Glu Asn Pro Asp Ile Glu Cys Ala Asp Cys Pro Ile Gly 435 440 445 Phe Tyr Asn Asp Pro His Asp Pro Arg Ser Cys Lys Pro Cys Pro Cys 450 455 460 His Asn Gly Phe Ser Cys Ser Val Met Pro Glu Thr Glu Glu Val Val 465 470 475 480 Cys Asn Asn Cys Pro Pro Gly Val Thr Gly Ala Arg Cys Glu Leu Cys 485 490 495 Ala Asp Gly Tyr Phe Gly Asp Pro Phe Gly Glu His Gly Pro Val Arg 500 505 510 Pro Cys Gln Pro Cys Gln Cys Asn Asn Asn Val Asp Pro Ser Ala Ser 515 520 525 Gly Asn Cys Asp Arg Leu Thr Gly Arg Cys Leu Lys Cys Ile His Asn 530 535 540 Thr Ala Gly Ile Tyr Cys Asp Gln Cys Lys Ala Gly Tyr Phe Gly Asp 545 550 555 560 Pro Leu Ala Pro Asn Pro Ala Asp Lys Cys Arg Ala Cys Asn Cys Asn 565 570 575 Pro Met Gly Ser Glu Pro Val Gly Cys Arg Ser Asp Gly Thr Cys Val 580 585 590 Cys Lys Pro Gly Phe Gly Gly Pro Asn Cys Glu His Gly Ala Phe Ser 595 600 605 Cys Pro Ala Cys Tyr Asn Gln Val Lys Ile Gln Met Asp Gln Phe Met 610 615 620 Gln Gln Leu Gln Arg Met Glu Ala Leu Ile Ser Lys Ala Gln Gly Gly 625 630 635 640 Asp Gly Val Val Pro Asp Thr Glu Leu Glu Gly Arg Met Gln Gln Ala 645 650 655 Glu Gln Ala Leu Gln Asp Ile Leu Arg Asp Ala Gln Ile Ser Glu Gly 660 665 670 Ala Ser Arg Ser Leu Gly Leu Gln Leu Ala Lys Val Arg Ser Gln Glu 675 680 685 Asn Ser Tyr Gln Ser Arg Leu Asp Asp Leu Lys Met Thr Val Glu Arg 690 695 700 Val Arg Ala Leu Gly Ser Gln Tyr Gln Asn Arg Val Arg Asp Thr His 705 710 715 720 Arg Leu Ile Thr Gln

Met Gln Leu Ser Leu Ala Glu Ser Glu Ala Ser 725 730 735 Leu Gly Asn Thr Asn Ile Pro Ala Ser Asp His Tyr Val Gly Pro Asn 740 745 750 Gly Phe Lys Ser Leu Ala Gln Glu Ala Thr Arg Leu Ala Glu Ser His 755 760 765 Val Glu Ser Ala Ser Asn Met Glu Gln Leu Thr Arg Glu Thr Glu Asp 770 775 780 Tyr Ser Lys Gln Ala Leu Ser Leu Val Arg Lys Ala Leu His Glu Gly 785 790 795 800 Val Gly Ser Gly Ser Gly Ser Pro Asp Gly Ala Val Val Gln Gly Leu 805 810 815 Val Glu Lys Leu Glu Lys Thr Lys Ser Leu Ala Gln Gln Leu Thr Arg 820 825 830 Glu Ala Thr Gln Ala Glu Ile Glu Ala Asp Arg Ser Tyr Gln His Ser 835 840 845 Leu Arg Leu Leu Asp Ser Val Ser Arg Leu Gln Gly Val Ser Asp Gln 850 855 860 Ser Phe Gln Val Glu Glu Ala Lys Arg Ile Lys Gln Lys Ala Asp Ser 865 870 875 880 Leu Ser Ser Leu Val Thr Arg His Met Asp Glu Phe Lys Arg Thr Gln 885 890 895 Lys Asn Leu Gly Asn Trp Lys Glu Glu Ala Gln Gln Leu Leu Gln Asn 900 905 910 Gly Lys Ser Gly Arg Glu Lys Ser Asp Gln Leu Leu Ser Arg Ala Asn 915 920 925 Leu Ala Lys Ser Arg Ala Gln Glu Ala Leu Ser Met Gly Asn Ala Thr 930 935 940 Phe Tyr Glu Val Glu Ser Ile Leu Lys Asn Leu Arg Glu Phe Asp Leu 945 950 955 960 Gln Val Asp Asn Arg Lys Ala Glu Ala Glu Glu Ala Met Lys Arg Leu 965 970 975 Ser Tyr Ile Ser Gln Lys Val Ser Asp Ala Ser Asp Lys Thr Gln Gln 980 985 990 Ala Glu Arg Ala Leu Gly Ser Ala Ala Ala Asp Ala Gln Arg Ala Lys 995 1000 1005 Asn Gly Ala Gly Glu Ala Leu Glu Ile Ser Ser Glu Ile Glu Gln 1010 1015 1020 Glu Ile Gly Ser Leu Asn Leu Glu Ala Asn Val Thr Ala Asp Gly 1025 1030 1035 Ala Leu Ala Met Glu Lys Gly Leu Ala Ser Leu Lys Ser Glu Met 1040 1045 1050 Arg Glu Val Glu Gly Glu Leu Glu Arg Lys Glu Leu Glu Phe Asp 1055 1060 1065 Thr Asn Met Asp Ala Val Gln Met Val Ile Thr Glu Ala Gln Lys 1070 1075 1080 Val Asp Thr Arg Ala Lys Asn Ala Gly Val Thr Ile Gln Asp Thr 1085 1090 1095 Leu Asn Thr Leu Asp Gly Leu Leu His Leu Met Gly Met 1100 1105 1110 40644PRTHomo sapiens 40Met Ser Arg Gln Phe Ser Ser Arg Ser Gly Tyr Arg Ser Gly Gly Gly 1 5 10 15 Phe Ser Ser Gly Ser Ala Gly Ile Ile Asn Tyr Gln Arg Arg Thr Thr 20 25 30 Ser Ser Ser Thr Arg Arg Ser Gly Gly Gly Gly Gly Arg Phe Ser Ser 35 40 45 Cys Gly Gly Gly Gly Gly Ser Phe Gly Ala Gly Gly Gly Phe Gly Ser 50 55 60 Arg Ser Leu Val Asn Leu Gly Gly Ser Lys Ser Ile Ser Ile Ser Val 65 70 75 80 Ala Arg Gly Gly Gly Arg Gly Ser Gly Phe Gly Gly Gly Tyr Gly Gly 85 90 95 Gly Gly Phe Gly Gly Gly Gly Phe Gly Gly Gly Gly Phe Gly Gly Gly 100 105 110 Gly Ile Gly Gly Gly Gly Phe Gly Gly Phe Gly Ser Gly Gly Gly Gly 115 120 125 Phe Gly Gly Gly Gly Phe Gly Gly Gly Gly Tyr Gly Gly Gly Tyr Gly 130 135 140 Pro Val Cys Pro Pro Gly Gly Ile Gln Glu Val Thr Ile Asn Gln Ser 145 150 155 160 Leu Leu Gln Pro Leu Asn Val Glu Ile Asp Pro Glu Ile Gln Lys Val 165 170 175 Lys Ser Arg Glu Arg Glu Gln Ile Lys Ser Leu Asn Asn Gln Phe Ala 180 185 190 Ser Phe Ile Asp Lys Val Arg Phe Leu Glu Gln Gln Asn Gln Val Leu 195 200 205 Gln Thr Lys Trp Glu Leu Leu Gln Gln Val Asp Thr Ser Thr Arg Thr 210 215 220 His Asn Leu Glu Pro Tyr Phe Glu Ser Phe Ile Asn Asn Leu Arg Arg 225 230 235 240 Arg Val Asp Gln Leu Lys Ser Asp Gln Ser Arg Leu Asp Ser Glu Leu 245 250 255 Lys Asn Met Gln Asp Met Val Glu Asp Tyr Arg Asn Lys Tyr Glu Asp 260 265 270 Glu Ile Asn Lys Arg Thr Asn Ala Glu Asn Glu Phe Val Thr Ile Lys 275 280 285 Lys Asp Val Asp Gly Ala Tyr Met Thr Lys Val Asp Leu Gln Ala Lys 290 295 300 Leu Asp Asn Leu Gln Gln Glu Ile Asp Phe Leu Thr Ala Leu Tyr Gln 305 310 315 320 Ala Glu Leu Ser Gln Met Gln Thr Gln Ile Ser Glu Thr Asn Val Ile 325 330 335 Leu Ser Met Asp Asn Asn Arg Ser Leu Asp Leu Asp Ser Ile Ile Ala 340 345 350 Glu Val Lys Ala Gln Tyr Glu Asp Ile Ala Gln Lys Ser Lys Ala Glu 355 360 365 Ala Glu Ser Leu Tyr Gln Ser Lys Tyr Glu Glu Leu Gln Ile Thr Ala 370 375 380 Gly Arg His Gly Asp Ser Val Arg Asn Ser Lys Ile Glu Ile Ser Glu 385 390 395 400 Leu Asn Arg Val Ile Gln Arg Leu Arg Ser Glu Ile Asp Asn Val Lys 405 410 415 Lys Gln Ile Ser Asn Leu Gln Gln Ser Ile Ser Asp Ala Glu Gln Arg 420 425 430 Gly Glu Asn Ala Leu Lys Asp Ala Lys Asn Lys Leu Asn Asp Leu Glu 435 440 445 Asp Ala Leu Gln Gln Ala Lys Glu Asp Leu Ala Arg Leu Leu Arg Asp 450 455 460 Tyr Gln Glu Leu Met Asn Thr Lys Leu Ala Leu Asp Leu Glu Ile Ala 465 470 475 480 Thr Tyr Arg Thr Leu Leu Glu Gly Glu Glu Ser Arg Met Ser Gly Glu 485 490 495 Cys Ala Pro Asn Val Ser Val Ser Val Ser Thr Ser His Thr Thr Ile 500 505 510 Ser Gly Gly Gly Ser Arg Gly Gly Gly Gly Gly Gly Tyr Gly Ser Gly 515 520 525 Gly Ser Ser Tyr Gly Ser Gly Gly Gly Ser Tyr Gly Ser Gly Gly Gly 530 535 540 Gly Gly Gly Gly Arg Gly Ser Tyr Gly Ser Gly Gly Ser Ser Tyr Gly 545 550 555 560 Ser Gly Gly Gly Ser Tyr Gly Ser Gly Gly Gly Gly Gly Gly His Gly 565 570 575 Ser Tyr Gly Ser Gly Ser Ser Ser Gly Gly Tyr Arg Gly Gly Ser Gly 580 585 590 Gly Gly Gly Gly Gly Ser Ser Gly Gly Arg Gly Ser Gly Gly Gly Ser 595 600 605 Ser Gly Gly Ser Ile Gly Gly Arg Gly Ser Ser Ser Gly Gly Val Lys 610 615 620 Ser Ser Gly Gly Ser Ser Ser Val Lys Phe Val Ser Thr Thr Tyr Ser 625 630 635 640 Gly Val Thr Arg 41298PRTHomo sapiens 41Met Thr Asp Ala Ala Val Ser Phe Ala Lys Asp Phe Leu Ala Gly Gly 1 5 10 15 Val Ala Ala Ala Ile Ser Lys Thr Ala Val Ala Pro Ile Glu Arg Val 20 25 30 Lys Leu Leu Leu Gln Val Gln His Ala Ser Lys Gln Ile Thr Ala Asp 35 40 45 Lys Gln Tyr Lys Gly Ile Ile Asp Cys Val Val Arg Ile Pro Lys Glu 50 55 60 Gln Gly Val Leu Ser Phe Trp Arg Gly Asn Leu Ala Asn Val Ile Arg 65 70 75 80 Tyr Phe Pro Thr Gln Ala Leu Asn Phe Ala Phe Lys Asp Lys Tyr Lys 85 90 95 Gln Ile Phe Leu Gly Gly Val Asp Lys Arg Thr Gln Phe Trp Leu Tyr 100 105 110 Phe Ala Gly Asn Leu Ala Ser Gly Gly Ala Ala Gly Ala Thr Ser Leu 115 120 125 Cys Phe Val Tyr Pro Leu Asp Phe Ala Arg Thr Arg Leu Ala Ala Asp 130 135 140 Val Gly Lys Ala Gly Ala Glu Arg Glu Phe Arg Gly Leu Gly Asp Cys 145 150 155 160 Leu Val Lys Ile Tyr Lys Ser Asp Gly Ile Lys Gly Leu Tyr Gln Gly 165 170 175 Phe Asn Val Ser Val Gln Gly Ile Ile Ile Tyr Arg Ala Ala Tyr Phe 180 185 190 Gly Ile Tyr Asp Thr Ala Lys Gly Met Leu Pro Asp Pro Lys Asn Thr 195 200 205 His Ile Val Ile Ser Trp Met Ile Ala Gln Thr Val Thr Ala Val Ala 210 215 220 Gly Leu Thr Ser Tyr Pro Phe Asp Thr Val Arg Arg Arg Met Met Met 225 230 235 240 Gln Ser Gly Arg Lys Gly Thr Asp Ile Met Tyr Thr Gly Thr Leu Asp 245 250 255 Cys Trp Arg Lys Ile Ala Arg Asp Glu Gly Gly Lys Ala Phe Phe Lys 260 265 270 Gly Ala Trp Ser Asn Val Leu Arg Gly Met Gly Gly Ala Phe Val Leu 275 280 285 Val Leu Tyr Asp Glu Ile Lys Lys Tyr Thr 290 295 42375PRTHomo sapiens 42Met Asp Asp Asp Ile Ala Ala Leu Val Val Asp Asn Gly Ser Gly Met 1 5 10 15 Cys Lys Ala Gly Phe Ala Gly Asp Asp Ala Pro Arg Ala Val Phe Pro 20 25 30 Ser Ile Val Gly Arg Pro Arg His Gln Gly Val Met Val Gly Met Gly 35 40 45 Gln Lys Asp Ser Tyr Val Gly Asp Glu Ala Gln Ser Lys Arg Gly Ile 50 55 60 Leu Thr Leu Lys Tyr Pro Ile Glu His Gly Ile Val Thr Asn Trp Asp 65 70 75 80 Asp Met Glu Lys Ile Trp His His Thr Phe Tyr Asn Glu Leu Arg Val 85 90 95 Ala Pro Glu Glu His Pro Val Leu Leu Thr Glu Ala Pro Leu Asn Pro 100 105 110 Lys Ala Asn Arg Glu Lys Met Thr Gln Ile Met Phe Glu Thr Phe Asn 115 120 125 Thr Pro Ala Met Tyr Val Ala Ile Gln Ala Val Leu Ser Leu Tyr Ala 130 135 140 Ser Gly Arg Thr Thr Gly Ile Val Met Asp Ser Gly Asp Gly Val Thr 145 150 155 160 His Thr Val Pro Ile Tyr Glu Gly Tyr Ala Leu Pro His Ala Ile Leu 165 170 175 Arg Leu Asp Leu Ala Gly Arg Asp Leu Thr Asp Tyr Leu Met Lys Ile 180 185 190 Leu Thr Glu Arg Gly Tyr Ser Phe Thr Thr Thr Ala Glu Arg Glu Ile 195 200 205 Val Arg Asp Ile Lys Glu Lys Leu Cys Tyr Val Ala Leu Asp Phe Glu 210 215 220 Gln Glu Met Ala Thr Ala Ala Ser Ser Ser Ser Leu Glu Lys Ser Tyr 225 230 235 240 Glu Leu Pro Asp Gly Gln Val Ile Thr Ile Gly Asn Glu Arg Phe Arg 245 250 255 Cys Pro Glu Ala Leu Phe Gln Pro Ser Phe Leu Gly Met Glu Ser Cys 260 265 270 Gly Ile His Glu Thr Thr Phe Asn Ser Ile Met Lys Cys Asp Val Asp 275 280 285 Ile Arg Lys Asp Leu Tyr Ala Asn Thr Val Leu Ser Gly Gly Thr Thr 290 295 300 Met Tyr Pro Gly Ile Ala Asp Arg Met Gln Lys Glu Ile Thr Ala Leu 305 310 315 320 Ala Pro Ser Thr Met Lys Ile Lys Ile Ile Ala Pro Pro Glu Arg Lys 325 330 335 Tyr Ser Val Trp Ile Gly Gly Ser Ile Leu Ala Ser Leu Ser Thr Phe 340 345 350 Gln Gln Met Trp Ile Ser Lys Gln Glu Tyr Asp Glu Ser Gly Pro Ser 355 360 365 Ile Val His Arg Lys Cys Phe 370 375 435090PRTHomo sapiens 43Met Ser Gly His Thr Leu Pro Pro Leu Pro Val Pro Gly Thr Asn Ser 1 5 10 15 Thr Glu Gln Ala Ser Val Pro Arg Ala Met Ala Ala Thr Leu Gly Ala 20 25 30 Gly Thr Pro Pro Arg Pro Gln Ala Arg Ser Ile Ala Gly Val Tyr Val 35 40 45 Glu Ala Ser Gly Gln Ala Gln Ser Val Tyr Ala Ala Met Glu Gln Gly 50 55 60 Leu Leu Pro Ala Gly Leu Gly Gln Ala Leu Leu Glu Ala Gln Ala Ala 65 70 75 80 Thr Gly Gly Leu Val Asp Leu Ala Arg Gly Gln Leu Leu Pro Val Ser 85 90 95 Lys Ala Leu Gln Gln Gly Leu Val Gly Leu Glu Leu Lys Glu Lys Leu 100 105 110 Leu Ala Ala Glu Arg Ala Thr Thr Gly Tyr Pro Asp Pro Tyr Gly Gly 115 120 125 Glu Lys Leu Ala Leu Phe Gln Ala Ile Gly Lys Glu Val Val Asp Arg 130 135 140 Ala Leu Gly Gln Ser Trp Leu Glu Val Gln Leu Ala Thr Gly Gly Leu 145 150 155 160 Val Asp Pro Ala Gln Gly Val Leu Val Ala Pro Glu Pro Ala Cys His 165 170 175 Gln Gly Leu Leu Asp Arg Glu Thr Trp His Lys Leu Ser Glu Leu Glu 180 185 190 Pro Gly Thr Gly Asp Leu Arg Phe Leu Asn Pro Asn Thr Leu Glu Arg 195 200 205 Leu Thr Tyr His Gln Leu Leu Glu Arg Cys Val Arg Ala Pro Gly Ser 210 215 220 Gly Leu Ala Leu Leu Pro Leu Lys Ile Thr Phe Arg Ser Met Gly Gly 225 230 235 240 Ala Val Ser Ala Ala Glu Leu Leu Glu Val Gly Ile Leu Asp Glu Gln 245 250 255 Ala Val Gln Gly Leu Arg Glu Gly Arg Leu Ala Ala Val Asp Val Ser 260 265 270 Ala Arg Ala Glu Val Arg Arg Tyr Leu Glu Gly Thr Gly Ser Val Ala 275 280 285 Gly Val Val Leu Leu Pro Glu Gly His Lys Lys Ser Phe Phe Gln Ala 290 295 300 Ala Thr Glu His Leu Leu Pro Met Gly Thr Ala Leu Pro Leu Leu Glu 305 310 315 320 Ala Gln Ala Ala Thr His Thr Leu Val Asp Pro Ile Thr Gly Gln Arg 325 330 335 Leu Trp Val Asp Glu Ala Val Arg Ala Gly Leu Val Ser Pro Glu Leu 340 345 350 His Glu Gln Leu Leu Val Ala Glu Gln Ala Val Thr Gly His His Asp 355 360 365 Pro Phe Ser Gly Ser Gln Ile Pro Leu Phe Gln Ala Met Lys Lys Gly 370 375 380 Leu Val Asp Arg Pro Leu Ala Leu Arg Leu Leu Asp Ala Gln Leu Ala 385 390 395 400 Thr Gly Gly Leu Val Cys Pro Ala Arg Arg Leu Arg Leu Pro Leu Glu 405 410 415 Ala Ala Leu Arg Cys Gly Cys Leu Asp Glu Asp Thr Gln Arg Gln Leu 420 425 430 Ser Gln Ala Gly Ser Phe Ser Asp Gly Thr His Gly Gly Leu Arg Tyr 435 440 445 Glu Gln Leu Leu Ala Leu Cys Val Thr Asp Pro Glu Thr Gly Leu Ala 450 455 460 Phe Leu Pro Leu Ser Gly Gly Pro Arg Gly Gly Glu Pro Gln Gly Pro 465 470 475 480 Pro Phe Ile Lys Tyr Ser Thr Arg Gln Ala Leu Ser Thr Ala Thr Ala 485 490 495 Thr Val Ser Val Gly Lys Phe Arg Gly Arg Pro Val Ser Leu Trp Glu 500 505 510 Leu Leu Phe Ser Glu Ala Ile Ser Ser Glu Gln Arg Ala Met Leu Ala 515 520 525 Gln Gln Tyr Gln Glu Gly Thr Leu Ser Val Glu Lys Leu Ala Ala Glu 530 535 540 Leu Ser Ala Thr Leu Glu Gln Ala Ala Ala Thr Ala Arg Val Thr Phe 545 550 555 560 Ser Gly Leu Arg Asp Thr Val Thr Pro Gly Glu Leu Leu Lys Ala Glu 565 570 575 Ile Ile Asp Gln Asp Leu Tyr Glu Arg Leu Glu His Gly Gln Ala Thr 580

585 590 Ala Lys Asp Val Gly Ser Leu Ala Ser Ala Gln Arg Tyr Leu Gln Gly 595 600 605 Thr Gly Cys Ile Ala Gly Leu Leu Leu Pro Gly Ser Gln Glu Arg Leu 610 615 620 Ser Ile Tyr Glu Ala Arg Cys Lys Gly Leu Leu Arg Pro Gly Thr Ala 625 630 635 640 Leu Ile Leu Leu Glu Ala Gln Ala Ala Thr Gly Phe Ile Ile Asp Pro 645 650 655 Lys Ala Asn Lys Gly His Ser Val Glu Glu Ala Leu Arg Ala Ala Val 660 665 670 Ile Gly Pro Asp Val Phe Ala Lys Leu Leu Ser Ala Glu Arg Ala Val 675 680 685 Thr Gly Tyr Thr Asp Pro Tyr Thr Gly Gln Gln Ile Ser Leu Phe Gln 690 695 700 Ala Met Gln Lys Gly Leu Ile Val Arg Glu His Gly Ile Arg Leu Leu 705 710 715 720 Glu Ala Gln Ile Ala Thr Gly Gly Val Ile Asp Pro Val His Ser His 725 730 735 Arg Val Pro Val Asp Val Ala Tyr Arg Arg Gly Tyr Phe Asp Gln Met 740 745 750 Leu Asn Leu Ile Leu Leu Asp Pro Ser Asp Asp Thr Lys Gly Phe Phe 755 760 765 Asp Pro Asn Thr His Glu Asn Leu Thr Tyr Leu Gln Leu Leu Glu Arg 770 775 780 Cys Val Arg Asp Pro Glu Thr Gly Leu Tyr Leu Leu Pro Leu Ser Ser 785 790 795 800 Thr Gln Ser Pro Leu Val Asp Ser Ala Thr Gln Gln Ala Phe Gln Asn 805 810 815 Leu Leu Leu Ser Val Lys Tyr Gly Arg Phe Gln Gly Gln Arg Val Ser 820 825 830 Ala Trp Glu Leu Ile Asn Ser Glu Tyr Phe Ser Glu Gly Arg Arg Arg 835 840 845 Gln Leu Leu Arg Arg Tyr Arg Gln Arg Glu Val Thr Leu Gly Gln Val 850 855 860 Ala Lys Leu Leu Glu Ala Glu Thr Gln Arg Gln Ala Asp Ile Met Leu 865 870 875 880 Pro Ala Leu Arg Ser Arg Val Thr Val His Gln Leu Leu Glu Ala Gly 885 890 895 Ile Ile Asp Gln Gln Leu Leu Asp Gln Val Leu Ala Gly Thr Ile Ser 900 905 910 Pro Glu Ala Leu Leu Leu Met Asp Gly Val Arg Arg Tyr Leu Cys Gly 915 920 925 Leu Gly Ala Val Gly Gly Val Arg Leu Leu Pro Ser Gly Gln Arg Leu 930 935 940 Ser Leu Tyr Gln Ala Met Arg Gln Lys Leu Leu Gly Pro Arg Val Ala 945 950 955 960 Leu Ala Leu Leu Glu Ala Gln Ala Ala Thr Gly Thr Ile Met Asp Pro 965 970 975 His Ser Pro Glu Ser Leu Ser Val Asp Glu Ala Val Arg Arg Gly Val 980 985 990 Val Gly Pro Glu Leu Tyr Gly Arg Leu Lys Arg Ala Glu Gly Ala Ile 995 1000 1005 Ala Gly Phe Arg Asp Pro Phe Ser Gly Lys Gln Val Ser Val Phe 1010 1015 1020 Gln Ala Met Lys Lys Gly Leu Ile Pro Trp Glu Gln Ala Ala Arg 1025 1030 1035 Leu Leu Glu Ala Gln Val Ala Thr Gly Gly Ile Ile Asp Pro Thr 1040 1045 1050 Ser His His His Leu Pro Met Pro Val Ala Ile Gln Arg Gly Tyr 1055 1060 1065 Val Asp Gln Glu Met Glu Thr Ala Leu Ser Ser Ser Ser Glu Thr 1070 1075 1080 Phe Pro Thr Pro Asp Gly Gln Gly Arg Thr Ser Tyr Ala Gln Leu 1085 1090 1095 Leu Glu Glu Cys Pro Arg Asp Glu Thr Ser Gly Leu His Leu Leu 1100 1105 1110 Pro Leu Pro Glu Ser Ala Pro Ala Leu Pro Thr Glu Glu Gln Val 1115 1120 1125 Gln Arg Ser Leu Gln Ala Val Pro Gly Ala Lys Asp Gly Thr Ser 1130 1135 1140 Leu Trp Asp Leu Leu Ser Ser Cys His Phe Thr Glu Glu Gln Arg 1145 1150 1155 Arg Gly Leu Leu Glu Asp Val Gln Glu Gly Arg Thr Thr Val Pro 1160 1165 1170 Gln Leu Leu Ala Ser Val Gln Arg Trp Val Gln Glu Thr Lys Leu 1175 1180 1185 Leu Ala Gln Ala Arg Val Met Val Pro Gly Pro Arg Gly Glu Val 1190 1195 1200 Pro Ala Val Trp Leu Leu Asp Ala Gly Ile Ile Thr Gln Glu Thr 1205 1210 1215 Leu Glu Ala Leu Ala Gln Gly Thr Gln Ser Pro Ala Gln Val Ala 1220 1225 1230 Glu Gln Pro Ala Val Lys Ala Cys Leu Trp Gly Thr Gly Cys Val 1235 1240 1245 Ala Gly Val Leu Leu Gln Pro Ser Gly Ala Lys Ala Ser Ile Ala 1250 1255 1260 Gln Ala Val Arg Asp Gly Leu Leu Pro Thr Gly Leu Gly Gln Arg 1265 1270 1275 Leu Leu Glu Ala Gln Val Ala Ser Gly Phe Leu Val Asp Pro Leu 1280 1285 1290 Asn Asn Gln Arg Leu Ser Val Glu Asp Ala Val Lys Val Gly Leu 1295 1300 1305 Val Gly Arg Glu Leu Ser Glu Gln Leu Gly Gln Ala Glu Arg Ala 1310 1315 1320 Ala Ala Gly Tyr Pro Asp Pro Tyr Ser Arg Ala Ser Leu Ser Leu 1325 1330 1335 Trp Gln Ala Met Glu Lys Gly Leu Val Pro Gln Asn Glu Gly Leu 1340 1345 1350 Pro Leu Leu Gln Val Gln Leu Ala Thr Gly Gly Val Val Asp Pro 1355 1360 1365 Val His Gly Val His Leu Pro Gln Ala Ala Ala Cys Arg Leu Gly 1370 1375 1380 Leu Leu Asp Thr Gln Thr Ser Gln Val Leu Thr Ala Val Asp Lys 1385 1390 1395 Asp Asn Lys Phe Phe Phe Asp Pro Ser Ala Arg Asp Gln Val Thr 1400 1405 1410 Tyr Gln Gln Leu Arg Glu Arg Cys Val Cys Asp Ser Glu Thr Gly 1415 1420 1425 Leu Leu Leu Leu Pro Leu Pro Ser Asp Thr Val Leu Glu Val Asp 1430 1435 1440 Asp His Thr Ala Val Ala Leu Arg Ala Met Lys Val Pro Val Ser 1445 1450 1455 Thr Gly Arg Phe Lys Gly Cys Ser Val Ser Leu Trp Asp Leu Leu 1460 1465 1470 Leu Ser Glu Tyr Val Gly Ala Asp Lys Arg Arg Glu Leu Val Ala 1475 1480 1485 Leu Cys Arg Ser Gly Arg Ala Ala Ala Leu Arg Gln Val Val Ser 1490 1495 1500 Ala Val Thr Ala Leu Val Glu Ala Ala Glu Arg Gln Pro Leu Gln 1505 1510 1515 Ala Thr Phe Arg Gly Leu Arg Lys Gln Val Ser Ala Arg Asp Leu 1520 1525 1530 Phe Arg Ala Gln Leu Ile Ser Arg Lys Thr Leu Asp Glu Leu Ser 1535 1540 1545 Gln Gly Thr Thr Thr Val Lys Glu Val Ala Glu Met Asp Ser Val 1550 1555 1560 Lys Arg Ser Leu Glu Gly Gly Asn Phe Ile Ala Gly Val Leu Ile 1565 1570 1575 Gln Gly Thr Gln Glu Arg Met Ser Ile Pro Glu Ala Leu Arg Arg 1580 1585 1590 His Ile Leu Arg Pro Gly Thr Ala Leu Val Leu Leu Glu Ala Gln 1595 1600 1605 Ala Ala Thr Gly Phe Ile Ile Asp Pro Ala Glu Asn Arg Lys Leu 1610 1615 1620 Thr Val Glu Glu Ala Phe Lys Ala Gly Met Phe Gly Lys Glu Thr 1625 1630 1635 Tyr Val Lys Leu Leu Ser Ala Glu Arg Ala Val Thr Gly Tyr Thr 1640 1645 1650 Asp Pro Tyr Thr Gly Gln Gln Ile Ser Leu Phe Gln Ala Met Gln 1655 1660 1665 Lys Asp Leu Ile Val Arg Glu His Gly Ile Arg Leu Leu Glu Ala 1670 1675 1680 Gln Ile Ala Thr Gly Gly Ile Ile Asp Pro Val His Ser His Arg 1685 1690 1695 Val Pro Val Asp Val Ala Tyr Arg Cys Gly Tyr Phe Asp Glu Glu 1700 1705 1710 Met Asn Arg Ile Leu Ala Asp Pro Ser Asp Asp Thr Lys Gly Phe 1715 1720 1725 Phe Asp Pro Asn Thr His Glu Asn Leu Thr Tyr Leu Gln Leu Leu 1730 1735 1740 Glu Arg Cys Val Glu Asp Pro Glu Thr Gly Leu Tyr Leu Leu Gln 1745 1750 1755 Ile Ile Lys Lys Gly Glu Asn Tyr Val Tyr Ile Asn Glu Ala Thr 1760 1765 1770 Arg His Val Leu Gln Ser Arg Thr Ala Lys Met Arg Val Gly Arg 1775 1780 1785 Phe Ala Asp Gln Val Val Ser Phe Trp Asp Leu Leu Ser Ser Pro 1790 1795 1800 Tyr Phe Thr Glu Asp Arg Lys Arg Glu Leu Ile Gln Glu Tyr Gly 1805 1810 1815 Ala Gln Ser Gly Gly Leu Glu Lys Leu Leu Glu Ile Ile Thr Thr 1820 1825 1830 Thr Ile Glu Glu Thr Glu Thr Gln Asn Gln Gly Ile Lys Val Ala 1835 1840 1845 Ala Ile Arg Gly Glu Val Thr Ala Ala Asp Leu Phe Asn Ser Arg 1850 1855 1860 Val Ile Asp Gln Lys Thr Leu His Thr Leu Arg Val Gly Arg Thr 1865 1870 1875 Gly Gly Gln Ala Leu Ser Thr Leu Glu Cys Val Lys Pro Tyr Leu 1880 1885 1890 Glu Gly Ser Asp Cys Ile Ala Gly Val Thr Val Pro Ser Thr Arg 1895 1900 1905 Glu Val Met Ser Leu His Glu Ala Ser Arg Lys Glu Leu Ile Pro 1910 1915 1920 Ala Ala Phe Ala Thr Trp Leu Leu Glu Ala Gln Ala Ala Thr Gly 1925 1930 1935 Phe Leu Leu Asp Pro Cys Thr Arg Gln Lys Leu Ser Val Asp Glu 1940 1945 1950 Ala Val Asp Val Gly Leu Val Asn Glu Glu Leu Arg Glu Arg Leu 1955 1960 1965 Leu Lys Ala Glu Arg Ala Ala Thr Gly Tyr Arg Asp Pro Ala Thr 1970 1975 1980 Gly Asp Thr Ile Pro Leu Phe Gln Ala Met Gln Lys Gln Leu Ile 1985 1990 1995 Glu Lys Ala Glu Ala Leu Arg Leu Leu Glu Val Gln Val Ala Thr 2000 2005 2010 Gly Gly Val Ile Asp Pro Gln His His His Arg Leu Pro Leu Glu 2015 2020 2025 Thr Ala Tyr Arg Arg Gly Cys Leu His Lys Asp Ile Tyr Ala Leu 2030 2035 2040 Ile Ser Asp Gln Lys His Met Arg Lys Arg Phe Val Asp Pro Asn 2045 2050 2055 Thr Gln Glu Lys Val Ser Tyr Arg Glu Leu Gln Glu Arg Cys Arg 2060 2065 2070 Pro Gln Glu Asp Thr Gly Trp Val Leu Phe Pro Val Asn Lys Ala 2075 2080 2085 Ala Arg Asp Ser Glu His Ile Asp Asp Glu Thr Arg Arg Ala Leu 2090 2095 2100 Glu Ala Glu Gln Val Glu Ile Thr Val Gly Arg Phe Arg Gly Gln 2105 2110 2115 Lys Pro Thr Leu Trp Ala Leu Leu Asn Ser Glu Tyr Val Thr Glu 2120 2125 2130 Glu Lys Lys Leu Gln Leu Val Arg Met Tyr Arg Thr His Thr Arg 2135 2140 2145 Arg Ala Leu Gln Thr Val Ala Gln Leu Ile Leu Glu Leu Ile Glu 2150 2155 2160 Lys Gln Glu Thr Ser Asn Lys His Leu Trp Phe Gln Gly Ile Arg 2165 2170 2175 Arg Gln Ile Thr Ala Ser Glu Leu Leu Ser Ser Ala Ile Ile Thr 2180 2185 2190 Glu Glu Met Leu Gln Asp Leu Glu Thr Gly Arg Ser Thr Thr Gln 2195 2200 2205 Glu Leu Met Glu Asp Asp Arg Val Lys Arg Tyr Leu Glu Gly Thr 2210 2215 2220 Ser Cys Ile Ala Gly Val Leu Val Pro Ala Lys Asp Gln Pro Gly 2225 2230 2235 Arg Gln Glu Lys Met Ser Ile Tyr Gln Ala Met Trp Lys Gly Val 2240 2245 2250 Leu Arg Pro Gly Thr Ala Leu Val Leu Leu Glu Ala Gln Ala Ala 2255 2260 2265 Thr Gly Phe Val Ile Asp Pro Val Arg Asn Leu Arg Leu Ser Val 2270 2275 2280 Glu Glu Pro Val Pro Ala Gly Val Val Gly Ser Glu Ile Gln Glu 2285 2290 2295 Lys Leu Leu Ser Ala Glu Arg Ala Val Thr Gly Tyr Thr Asp Pro 2300 2305 2310 Tyr Thr Gly Gln Gln Ile Ser Leu Phe Gln Ala Met Gln Lys Asp 2315 2320 2325 Leu Ile Val Arg Glu His Gly Ile Arg Leu Leu Glu Ala Gln Ile 2330 2335 2340 Ala Thr Gly Gly Val Ile Asp Pro Val His Ser His Arg Val Pro 2345 2350 2355 Val Asp Val Ala Tyr Arg Arg Gly Tyr Phe Asp Glu Glu Met Asn 2360 2365 2370 Arg Val Leu Ala Asp Pro Ser Asp Asp Thr Lys Gly Phe Phe Asp 2375 2380 2385 Pro Asn Thr His Glu Asn Leu Thr Tyr Val Gln Leu Leu Arg Arg 2390 2395 2400 Cys Val Pro Asp Pro Asp Thr Gly Leu Tyr Met Leu Gln Leu Ala 2405 2410 2415 Gly Arg Gly Ser Ala Val His Gln Leu Ser Glu Glu Leu Arg Cys 2420 2425 2430 Ala Leu Arg Asp Ala Arg Val Thr Pro Gly Ser Gly Ala Leu Gln 2435 2440 2445 Gly Gln Ser Val Ser Val Trp Glu Leu Leu Phe Tyr Arg Glu Val 2450 2455 2460 Ser Glu Asp Arg Arg Gln Asp Leu Leu Ser Arg Tyr Arg Ala Gly 2465 2470 2475 Thr Leu Thr Val Glu Glu Leu Gly Ala Thr Leu Thr Ser Leu Leu 2480 2485 2490 Ala Gln Ala Gln Ala Gln Ala Arg Ala Glu Ala Glu Ala Gly Ser 2495 2500 2505 Pro Arg Pro Asp Pro Arg Glu Ala Leu Arg Ala Ala Thr Met Glu 2510 2515 2520 Val Lys Val Gly Arg Leu Arg Gly Arg Ala Val Pro Val Trp Asp 2525 2530 2535 Val Leu Ala Ser Gly Tyr Val Ser Arg Ala Ala Arg Glu Glu Leu 2540 2545 2550 Leu Ala Glu Phe Gly Ser Gly Thr Leu Asp Leu Pro Ala Leu Thr 2555 2560 2565 Arg Arg Leu Thr Ala Ile Ile Glu Glu Ala Glu Glu Ala Pro Gly 2570 2575 2580 Ala Arg Pro Gln Leu Gln Asp Ala Arg Arg Gly Pro Arg Glu Pro 2585 2590 2595 Gly Pro Ala Gly Arg Gly Asp Gly Asp Ser Gly Arg Ser Gln Arg 2600 2605 2610 Glu Gly Gln Gly Glu Gly Glu Thr Gln Glu Ala Ala Ala Ala Ala 2615 2620 2625 Ala Ala Ala Arg Arg Gln Glu Gln Thr Leu Arg Asp Ala Thr Met 2630 2635 2640 Glu Val Gln Arg Gly Gln Phe Gln Gly Arg Pro Val Ser Val Trp 2645 2650 2655 Asp Val Leu Phe Ser Ser Tyr Leu Ser Glu Ala Arg Arg Asp Glu 2660 2665 2670 Leu Leu Ala Gln His Ala Ala Gly Ala Leu Gly Leu Pro Asp Leu 2675 2680 2685 Val Ala Val Leu Thr Arg Val Ile Glu Glu Thr Glu Glu Arg Leu 2690 2695 2700 Ser Lys Val Ser Phe Arg Gly Leu Arg Arg Gln Val Ser Ala Ser 2705 2710 2715 Glu Leu His Thr Ser Gly Ile Leu Gly Pro Glu Thr Leu Arg Asp 2720 2725 2730 Leu Ala Gln Gly Thr Lys Thr Leu Gln Glu Val Thr Glu Met Asp 2735 2740 2745 Ser Val Lys Arg Tyr Leu Glu Gly Thr Ser Cys Ile Ala Gly Val 2750 2755 2760 Leu Val Pro Ala Lys Asp Gln Pro Gly Arg Gln Glu Lys Met Ser 2765 2770 2775 Ile Tyr Gln Ala Met Trp Lys Gly Val Leu Arg Pro Gly Thr Ala 2780 2785 2790 Leu Val Leu Leu Glu Ala Gln Ala Ala Thr Gly Phe Val Ile Asp 2795

2800 2805 Pro Val Arg Asn Leu Arg Leu Ser Val Glu Glu Ala Val Ala Ala 2810 2815 2820 Gly Val Val Gly Gly Glu Ile Gln Glu Lys Leu Leu Ser Ala Glu 2825 2830 2835 Arg Ala Val Thr Gly Tyr Thr Asp Pro Tyr Thr Gly Gln Gln Ile 2840 2845 2850 Ser Leu Phe Gln Ala Met Gln Lys Asp Leu Ile Val Arg Glu His 2855 2860 2865 Gly Ile Arg Leu Leu Glu Ala Gln Ile Ala Thr Gly Gly Val Ile 2870 2875 2880 Asp Pro Val His Ser His Arg Val Pro Val Asp Val Ala Tyr Arg 2885 2890 2895 Arg Gly Tyr Phe Asp Glu Glu Met Asn Arg Val Leu Ala Asp Pro 2900 2905 2910 Ser Asp Asp Thr Lys Gly Phe Phe Asp Pro Asn Thr His Glu Asn 2915 2920 2925 Leu Thr Tyr Val Gln Leu Leu Arg Arg Cys Val Pro Asp Pro Asp 2930 2935 2940 Thr Gly Leu Tyr Met Leu Gln Leu Ala Gly Arg Gly Ser Ala Val 2945 2950 2955 His Gln Leu Ser Glu Glu Leu Arg Cys Ala Leu Arg Asp Ala Arg 2960 2965 2970 Val Thr Pro Gly Ser Gly Ala Leu Gln Gly Gln Ser Val Ser Val 2975 2980 2985 Trp Glu Leu Leu Phe Tyr Arg Glu Val Ser Glu Asp Arg Arg Gln 2990 2995 3000 Asp Leu Leu Ser Arg Tyr Arg Ala Gly Thr Leu Thr Val Glu Glu 3005 3010 3015 Leu Gly Ala Thr Leu Thr Ser Leu Leu Ala Gln Ala Gln Ala Gln 3020 3025 3030 Ala Arg Ala Glu Ala Glu Ala Gly Ser Pro Arg Pro Asp Pro Arg 3035 3040 3045 Glu Ala Leu Arg Ala Ala Thr Met Glu Val Lys Val Gly Arg Leu 3050 3055 3060 Arg Gly Arg Ala Val Pro Val Trp Asp Val Leu Ala Ser Gly Tyr 3065 3070 3075 Val Ser Gly Ala Ala Arg Glu Glu Leu Leu Ala Glu Phe Gly Ser 3080 3085 3090 Gly Thr Leu Asp Leu Pro Ala Leu Thr Arg Arg Leu Thr Ala Ile 3095 3100 3105 Ile Glu Glu Ala Glu Glu Ala Pro Gly Ala Arg Pro Gln Leu Gln 3110 3115 3120 Asp Ala Trp Arg Gly Pro Arg Glu Pro Gly Pro Ala Gly Arg Gly 3125 3130 3135 Asp Gly Asp Ser Gly Arg Ser Gln Arg Glu Gly Gln Gly Glu Gly 3140 3145 3150 Glu Thr Gln Glu Ala Ala Ala Ala Ala Ala Ala Ala Arg Arg Gln 3155 3160 3165 Glu Gln Thr Leu Arg Asp Ala Thr Met Glu Val Gln Arg Gly Gln 3170 3175 3180 Phe Gln Gly Arg Pro Val Ser Val Trp Asp Val Leu Phe Ser Ser 3185 3190 3195 Tyr Leu Ser Glu Ala Arg Arg Asp Glu Leu Leu Ala Gln His Ala 3200 3205 3210 Ala Gly Ala Leu Gly Leu Pro Asp Leu Val Ala Val Leu Thr Arg 3215 3220 3225 Val Ile Glu Glu Thr Glu Glu Arg Leu Ser Lys Val Ser Phe Arg 3230 3235 3240 Gly Leu Arg Arg Gln Val Ser Ala Ser Glu Leu His Thr Ser Gly 3245 3250 3255 Ile Leu Gly Pro Glu Thr Leu Arg Asp Leu Ala Gln Gly Thr Lys 3260 3265 3270 Thr Leu Gln Glu Val Thr Glu Met Asp Ser Val Lys Arg Tyr Leu 3275 3280 3285 Glu Gly Thr Ser Cys Ile Ala Gly Val Leu Val Pro Ala Lys Asp 3290 3295 3300 Gln Pro Gly Arg Gln Glu Lys Met Ser Ile Tyr Gln Ala Met Trp 3305 3310 3315 Lys Gly Val Leu Arg Pro Gly Thr Ala Leu Val Leu Leu Glu Ala 3320 3325 3330 Gln Ala Ala Thr Gly Phe Val Ile Asp Pro Val Arg Asn Leu Arg 3335 3340 3345 Leu Ser Val Glu Glu Ala Val Ala Ala Gly Val Val Gly Gly Glu 3350 3355 3360 Ile Gln Glu Lys Leu Leu Ser Ala Glu Arg Ala Val Thr Gly Tyr 3365 3370 3375 Thr Asp Pro Tyr Thr Gly Gln Gln Ile Ser Leu Phe Gln Ala Met 3380 3385 3390 Gln Lys Asp Leu Ile Val Arg Glu His Gly Ile Arg Leu Leu Glu 3395 3400 3405 Ala Gln Ile Ala Thr Gly Gly Val Ile Asp Pro Val His Ser His 3410 3415 3420 Arg Val Pro Val Asp Val Ala Tyr Arg Arg Gly Tyr Phe Asp Glu 3425 3430 3435 Glu Met Asn Arg Val Leu Ala Asp Pro Ser Asp Asp Thr Lys Gly 3440 3445 3450 Phe Phe Asp Pro Asn Thr His Glu Asn Leu Thr Tyr Val Gln Leu 3455 3460 3465 Leu Arg Arg Cys Val Pro Asp Pro Asp Thr Gly Leu Tyr Met Leu 3470 3475 3480 Gln Leu Ala Gly Arg Gly Ser Ala Val His Gln Leu Ser Glu Glu 3485 3490 3495 Leu Arg Cys Ala Leu Arg Asp Ala Arg Val Thr Pro Gly Ser Gly 3500 3505 3510 Ala Leu Gln Gly Gln Ser Val Ser Val Trp Glu Leu Leu Phe Tyr 3515 3520 3525 Arg Glu Val Ser Glu Asp Arg Arg Gln Asp Leu Leu Ser Arg Tyr 3530 3535 3540 Arg Ala Gly Thr Leu Thr Val Glu Glu Leu Gly Ala Thr Leu Thr 3545 3550 3555 Ser Leu Leu Ala Gln Ala Gln Ala Gln Ala Arg Ala Glu Ala Glu 3560 3565 3570 Ala Gly Ser Pro Arg Pro Asp Pro Arg Glu Ala Leu Arg Ala Ala 3575 3580 3585 Thr Met Glu Val Lys Val Gly Arg Leu Arg Gly Arg Ala Val Pro 3590 3595 3600 Val Trp Asp Val Leu Ala Ser Gly Tyr Val Ser Gly Ala Ala Arg 3605 3610 3615 Glu Glu Leu Leu Ala Glu Phe Gly Ser Gly Thr Leu Asp Leu Pro 3620 3625 3630 Ala Leu Thr Arg Arg Leu Thr Ala Ile Ile Glu Glu Ala Glu Glu 3635 3640 3645 Ala Pro Gly Ala Arg Pro Gln Leu Gln Asp Ala Trp Arg Gly Pro 3650 3655 3660 Arg Glu Pro Gly Pro Ala Gly Arg Gly Asp Gly Asp Ser Gly Arg 3665 3670 3675 Ser Gln Arg Glu Gly Gln Gly Glu Gly Glu Thr Gln Glu Ala Ala 3680 3685 3690 Ala Ala Ala Ala Ala Ala Arg Arg Gln Glu Gln Thr Leu Arg Asp 3695 3700 3705 Ala Thr Met Glu Val Gln Arg Gly Gln Phe Gln Gly Arg Pro Val 3710 3715 3720 Ser Val Trp Asp Val Leu Phe Ser Ser Tyr Leu Ser Glu Ala Arg 3725 3730 3735 Arg Asp Glu Leu Leu Ala Gln His Ala Ala Gly Ala Leu Gly Leu 3740 3745 3750 Pro Asp Leu Val Ala Val Leu Thr Arg Val Ile Glu Glu Thr Glu 3755 3760 3765 Glu Arg Leu Ser Lys Val Ser Phe Arg Gly Leu Arg Arg Gln Val 3770 3775 3780 Ser Ala Ser Glu Leu His Thr Ser Gly Ile Leu Gly Pro Glu Thr 3785 3790 3795 Leu Arg Asp Leu Ala Gln Gly Thr Lys Thr Leu Gln Glu Val Thr 3800 3805 3810 Glu Met Asp Ser Val Lys Arg Tyr Leu Glu Gly Thr Ser Cys Ile 3815 3820 3825 Ala Gly Val Leu Val Pro Ala Lys Asp Gln Pro Gly Arg Gln Glu 3830 3835 3840 Lys Met Ser Ile Tyr Gln Ala Met Trp Lys Gly Val Leu Arg Pro 3845 3850 3855 Gly Thr Ala Leu Val Leu Leu Glu Ala Gln Ala Ala Thr Gly Phe 3860 3865 3870 Val Ile Asp Pro Val Arg Asn Leu Arg Leu Ser Val Glu Glu Ala 3875 3880 3885 Val Ala Ala Gly Val Val Gly Gly Glu Ile Gln Glu Lys Leu Leu 3890 3895 3900 Ser Ala Glu Arg Ala Val Thr Gly Tyr Thr Asp Pro Tyr Thr Gly 3905 3910 3915 Gln Gln Ile Ser Leu Phe Gln Ala Met Gln Lys Asp Leu Ile Val 3920 3925 3930 Arg Glu His Gly Ile Arg Leu Leu Glu Ala Gln Ile Ala Thr Gly 3935 3940 3945 Gly Val Ile Asp Pro Val His Ser His Arg Val Pro Val Asp Val 3950 3955 3960 Ala Tyr Arg Arg Gly Tyr Phe Asp Glu Glu Met Asn Arg Val Leu 3965 3970 3975 Ala Asp Pro Ser Asp Asp Thr Lys Gly Phe Phe Asp Pro Asn Thr 3980 3985 3990 His Glu Asn Leu Thr Tyr Val Gln Leu Leu Arg Arg Cys Val Pro 3995 4000 4005 Asp Pro Asp Thr Gly Leu Tyr Met Leu Gln Leu Ala Gly Arg Gly 4010 4015 4020 Ser Ala Val His Gln Leu Ser Glu Glu Leu Arg Cys Ala Leu Arg 4025 4030 4035 Asp Ala Arg Val Thr Pro Gly Ser Gly Ala Leu Gln Gly Gln Ser 4040 4045 4050 Val Ser Val Trp Glu Leu Leu Phe Tyr Arg Glu Val Ser Glu Asp 4055 4060 4065 Arg Arg Gln Asp Leu Leu Ser Arg Tyr Arg Ala Ser Thr Leu Thr 4070 4075 4080 Val Glu Glu Leu Gly Ala Thr Leu Thr Ser Leu Leu Ala Gln Ala 4085 4090 4095 Gln Ala Gln Ala Arg Ala Glu Ala Glu Ala Gly Ser Pro Arg Pro 4100 4105 4110 Asp Pro Arg Glu Ala Leu Arg Ala Ala Thr Met Glu Val Lys Val 4115 4120 4125 Gly Arg Leu Arg Gly Arg Ala Val Pro Val Trp Asp Val Leu Ala 4130 4135 4140 Ser Gly Tyr Val Ser Arg Ala Ala Arg Glu Glu Leu Leu Ala Glu 4145 4150 4155 Phe Gly Ser Gly Thr Leu Asp Leu Pro Ala Leu Thr Arg Arg Leu 4160 4165 4170 Thr Ala Ile Ile Glu Glu Ala Glu Glu Ala Pro Gly Ala Arg Pro 4175 4180 4185 Gln Leu Gln Asp Ala Trp Arg Gly Pro Arg Glu Pro Gly Pro Ala 4190 4195 4200 Gly Arg Gly Asp Gly Asp Ser Gly Arg Ser Gln Arg Glu Gly Gln 4205 4210 4215 Gly Glu Gly Glu Thr Gln Glu Ala Ala Ala Ala Thr Ala Ala Ala 4220 4225 4230 Arg Arg Gln Glu Gln Thr Leu Arg Asp Ala Thr Met Glu Val Gln 4235 4240 4245 Arg Gly Gln Phe Gln Gly Arg Pro Val Ser Val Trp Asp Val Leu 4250 4255 4260 Phe Ser Ser Tyr Leu Ser Glu Ala Arg Arg Asp Glu Leu Leu Ala 4265 4270 4275 Gln His Ala Ala Gly Ala Leu Gly Leu Pro Asp Leu Val Ala Val 4280 4285 4290 Leu Thr Arg Val Ile Glu Glu Thr Glu Glu Arg Leu Ser Lys Val 4295 4300 4305 Ser Phe Arg Gly Leu Arg Arg Gln Val Ser Ala Ser Glu Leu His 4310 4315 4320 Thr Ser Gly Ile Leu Gly Pro Glu Thr Leu Arg Asp Leu Ala Gln 4325 4330 4335 Gly Thr Lys Thr Leu Gln Glu Val Thr Glu Met Asp Ser Val Lys 4340 4345 4350 Arg Tyr Leu Glu Gly Thr Ser Cys Ile Ala Gly Val Leu Val Pro 4355 4360 4365 Ala Lys Asp Gln Pro Gly Arg Gln Glu Lys Met Ser Ile Tyr Gln 4370 4375 4380 Ala Met Trp Lys Gly Val Leu Arg Pro Gly Thr Ala Leu Val Leu 4385 4390 4395 Leu Glu Ala Gln Ala Ala Thr Gly Phe Val Ile Asp Pro Val Arg 4400 4405 4410 Asn Leu Arg Leu Ser Val Glu Glu Ala Val Ala Ala Gly Val Val 4415 4420 4425 Gly Gly Glu Ile Gln Glu Lys Leu Leu Ser Ala Glu Arg Ala Val 4430 4435 4440 Thr Gly Tyr Thr Asp Pro Tyr Thr Gly Gln Gln Ile Ser Leu Phe 4445 4450 4455 Gln Ala Met Gln Lys Asp Leu Ile Val Arg Glu His Gly Ile Arg 4460 4465 4470 Leu Leu Glu Ala Gln Ile Ala Thr Gly Gly Val Ile Asp Pro Val 4475 4480 4485 His Ser His Arg Val Pro Val Asp Val Ala Tyr Arg Arg Gly Tyr 4490 4495 4500 Phe Asp Glu Glu Met Asn Arg Val Leu Ala Asp Pro Ser Asp Asp 4505 4510 4515 Thr Lys Gly Phe Phe Asp Pro Asn Thr His Glu Asn Leu Thr Tyr 4520 4525 4530 Val Gln Leu Leu Arg Arg Cys Val Pro Asp Pro Asp Thr Gly Leu 4535 4540 4545 Tyr Met Leu Gln Leu Ala Gly Arg Gly Ser Ala Val His Gln Leu 4550 4555 4560 Ser Glu Glu Leu Arg Cys Ala Leu Arg Asp Ala Arg Val Thr Pro 4565 4570 4575 Gly Ser Gly Ala Leu Gln Gly Gln Ser Val Ser Val Trp Glu Leu 4580 4585 4590 Leu Phe Tyr Arg Glu Val Ser Glu Asp Arg Arg Gln Asp Leu Leu 4595 4600 4605 Ser Arg Tyr Arg Ala Gly Thr Leu Thr Val Glu Glu Leu Gly Ala 4610 4615 4620 Thr Leu Thr Ser Leu Leu Ala Gln Ala Gln Ala Gln Ala Arg Ala 4625 4630 4635 Glu Ala Glu Ala Gly Ser Pro Arg Pro Asp Pro Arg Glu Ala Leu 4640 4645 4650 Arg Ala Ala Thr Met Glu Val Lys Val Gly Arg Leu Arg Gly Arg 4655 4660 4665 Ala Val Pro Val Trp Asp Val Leu Ala Ser Gly Tyr Val Ser Gly 4670 4675 4680 Ala Ala Arg Glu Glu Leu Leu Ala Glu Phe Gly Ser Gly Thr Leu 4685 4690 4695 Asp Leu Pro Ala Leu Thr Arg Arg Leu Thr Ala Ile Ile Glu Glu 4700 4705 4710 Ala Glu Glu Ala Pro Gly Ala Arg Pro Gln Leu Gln Asp Ala Trp 4715 4720 4725 Arg Gly Pro Arg Glu Pro Gly Pro Ala Gly Arg Gly Asp Gly Asp 4730 4735 4740 Ser Gly Arg Ser Gln Arg Glu Gly Gln Gly Glu Gly Glu Thr Gln 4745 4750 4755 Glu Ala Ala Ala Ala Ala Ala Ala Ala Arg Arg Gln Glu Gln Thr 4760 4765 4770 Leu Arg Asp Ala Thr Met Glu Val Gln Arg Gly Gln Phe Gln Gly 4775 4780 4785 Arg Pro Val Ser Val Trp Asp Val Leu Phe Ser Ser Tyr Leu Ser 4790 4795 4800 Glu Ala Arg Arg Asp Glu Leu Leu Ala Gln His Ala Ala Gly Ala 4805 4810 4815 Leu Gly Leu Pro Asp Leu Val Ala Val Leu Thr Arg Val Ile Glu 4820 4825 4830 Glu Thr Glu Glu Arg Leu Ser Lys Val Ser Phe Arg Gly Leu Arg 4835 4840 4845 Arg Gln Val Ser Ala Ser Glu Leu His Thr Ser Gly Ile Leu Gly 4850 4855 4860 Pro Glu Thr Leu Arg Asp Leu Ala Gln Gly Thr Lys Thr Leu Gln 4865 4870 4875 Glu Val Thr Glu Met Asp Ser Val Lys Arg Tyr Leu Glu Gly Thr 4880 4885 4890 Ser Cys Ile Ala Gly Val Leu Val Pro Ala Lys Asp Gln Pro Gly 4895 4900 4905 Arg Gln Glu Lys Met Ser Ile Tyr Gln Ala Met Trp Lys Gly Val 4910 4915 4920 Leu Arg Pro Gly Thr Ala Leu Val Leu Leu Glu Ala Gln Ala Ala 4925 4930 4935 Thr Gly Phe Val Ile Asp Pro Val Arg Asn Leu Arg Leu Ser Val 4940 4945 4950 Glu Glu Ala Val Ala Ala Gly Val Val Gly Gly Glu Ile Gln Glu 4955 4960 4965 Lys Leu Leu Ser Ala Glu Arg Ala Val Thr Gly Tyr Thr Asp Pro 4970 4975 4980 Tyr Thr Gly Gln Gln Ile Ser Leu Phe Gln Ala Met Gln Lys Asp 4985 4990 4995

Leu Ile Val Arg Glu His Gly Ile Arg Leu Leu Glu Ala Gln Ile 5000 5005 5010 Ala Thr Gly Gly Val Ile Asp Pro Val His Ser His Arg Val Pro 5015 5020 5025 Val Asp Val Ala Tyr Arg Arg Gly Tyr Phe Asp Glu Glu Met Asn 5030 5035 5040 Arg Val Leu Ala Asp Pro Ser Asp Asp Thr Lys Gly Phe Phe Asp 5045 5050 5055 Pro Asn Thr His Glu Asn Leu Thr Tyr Leu Gln Leu Leu Gln Arg 5060 5065 5070 Ala Thr Leu Asp Pro Glu Thr Gly Leu Leu Phe Leu Ser Leu Ser 5075 5080 5085 Leu Gln 5090 44166PRTHomo sapiens 44Met Ala Ser Gly Val Ala Val Ser Asp Gly Val Ile Lys Val Phe Asn 1 5 10 15 Asp Met Lys Val Arg Lys Ser Ser Thr Pro Glu Glu Val Lys Lys Arg 20 25 30 Lys Lys Ala Val Leu Phe Cys Leu Ser Glu Asp Lys Lys Asn Ile Ile 35 40 45 Leu Glu Glu Gly Lys Glu Ile Leu Val Gly Asp Val Gly Gln Thr Val 50 55 60 Asp Asp Pro Tyr Ala Thr Phe Val Lys Met Leu Pro Asp Lys Asp Cys 65 70 75 80 Arg Tyr Ala Leu Tyr Asp Ala Thr Tyr Glu Thr Lys Glu Ser Lys Lys 85 90 95 Glu Asp Leu Val Phe Ile Phe Trp Ala Pro Glu Ser Ala Pro Leu Lys 100 105 110 Ser Lys Met Ile Tyr Ala Ser Ser Lys Asp Ala Ile Lys Lys Lys Leu 115 120 125 Thr Gly Ile Lys His Glu Leu Gln Ala Asn Cys Tyr Glu Glu Val Lys 130 135 140 Asp Arg Cys Thr Leu Ala Glu Lys Leu Gly Gly Ser Ala Val Ile Ser 145 150 155 160 Leu Glu Gly Lys Pro Leu 165 451172PRTHomo sapiens 45Met Arg Pro Phe Phe Leu Leu Cys Phe Ala Leu Pro Gly Leu Leu His 1 5 10 15 Ala Gln Gln Ala Cys Ser Arg Gly Ala Cys Tyr Pro Pro Val Gly Asp 20 25 30 Leu Leu Val Gly Arg Thr Arg Phe Leu Arg Ala Ser Ser Thr Cys Gly 35 40 45 Leu Thr Lys Pro Glu Thr Tyr Cys Thr Gln Tyr Gly Glu Trp Gln Met 50 55 60 Lys Cys Cys Lys Cys Asp Ser Arg Gln Pro His Asn Tyr Tyr Ser His 65 70 75 80 Arg Val Glu Asn Val Ala Ser Ser Ser Gly Pro Met Arg Trp Trp Gln 85 90 95 Ser Gln Asn Asp Val Asn Pro Val Ser Leu Gln Leu Asp Leu Asp Arg 100 105 110 Arg Phe Gln Leu Gln Glu Val Met Met Glu Phe Gln Gly Pro Met Pro 115 120 125 Ala Gly Met Leu Ile Glu Arg Ser Ser Asp Phe Gly Lys Thr Trp Arg 130 135 140 Val Tyr Gln Tyr Leu Ala Ala Asp Cys Thr Ser Thr Phe Pro Arg Val 145 150 155 160 Arg Gln Gly Arg Pro Gln Ser Trp Gln Asp Val Arg Cys Gln Ser Leu 165 170 175 Pro Gln Arg Pro Asn Ala Arg Leu Asn Gly Gly Lys Val Gln Leu Asn 180 185 190 Leu Met Asp Leu Val Ser Gly Ile Pro Ala Thr Gln Ser Gln Lys Ile 195 200 205 Gln Glu Val Gly Glu Ile Thr Asn Leu Arg Val Asn Phe Thr Arg Leu 210 215 220 Ala Pro Val Pro Gln Arg Gly Tyr His Pro Pro Ser Ala Tyr Tyr Ala 225 230 235 240 Val Ser Gln Leu Arg Leu Gln Gly Ser Cys Phe Cys His Gly His Ala 245 250 255 Asp Arg Cys Ala Pro Lys Pro Gly Ala Ser Ala Gly Pro Ser Thr Ala 260 265 270 Val Gln Val His Asp Val Cys Val Cys Gln His Asn Thr Ala Gly Pro 275 280 285 Asn Cys Glu Arg Cys Ala Pro Phe Tyr Asn Asn Arg Pro Trp Arg Pro 290 295 300 Ala Glu Gly Gln Asp Ala His Glu Cys Gln Arg Cys Asp Cys Asn Gly 305 310 315 320 His Ser Glu Thr Cys His Phe Asp Pro Ala Val Phe Ala Ala Ser Gln 325 330 335 Gly Ala Tyr Gly Gly Val Cys Asp Asn Cys Arg Asp His Thr Glu Gly 340 345 350 Lys Asn Cys Glu Arg Cys Gln Leu His Tyr Phe Arg Asn Arg Arg Pro 355 360 365 Gly Ala Ser Ile Gln Glu Thr Cys Ile Ser Cys Glu Cys Asp Pro Asp 370 375 380 Gly Ala Val Pro Gly Ala Pro Cys Asp Pro Val Thr Gly Gln Cys Val 385 390 395 400 Cys Lys Glu His Val Gln Gly Glu Arg Cys Asp Leu Cys Lys Pro Gly 405 410 415 Phe Thr Gly Leu Thr Tyr Ala Asn Pro Gln Gly Cys His Arg Cys Asp 420 425 430 Cys Asn Ile Leu Gly Ser Arg Arg Asp Met Pro Cys Asp Glu Glu Ser 435 440 445 Gly Arg Cys Leu Cys Leu Pro Asn Val Val Gly Pro Lys Cys Asp Gln 450 455 460 Cys Ala Pro Tyr His Trp Lys Leu Ala Ser Gly Gln Gly Cys Glu Pro 465 470 475 480 Cys Ala Cys Asp Pro His Asn Ser Leu Ser Pro Gln Cys Asn Gln Phe 485 490 495 Thr Gly Gln Cys Pro Cys Arg Glu Gly Phe Gly Gly Leu Met Cys Ser 500 505 510 Ala Ala Ala Ile Arg Gln Cys Pro Asp Arg Thr Tyr Gly Asp Val Ala 515 520 525 Thr Gly Cys Arg Ala Cys Asp Cys Asp Phe Arg Gly Thr Glu Gly Pro 530 535 540 Gly Cys Asp Lys Ala Ser Gly Arg Cys Leu Cys Arg Pro Gly Leu Thr 545 550 555 560 Gly Pro Arg Cys Asp Gln Cys Gln Arg Gly Tyr Cys Asn Arg Tyr Pro 565 570 575 Val Cys Val Ala Cys His Pro Cys Phe Gln Thr Tyr Asp Ala Asp Leu 580 585 590 Arg Glu Gln Ala Leu Arg Phe Gly Arg Leu Arg Asn Ala Thr Ala Ser 595 600 605 Leu Trp Ser Gly Pro Gly Leu Glu Asp Arg Gly Leu Ala Ser Arg Ile 610 615 620 Leu Asp Ala Lys Ser Lys Ile Glu Gln Ile Arg Ala Val Leu Ser Ser 625 630 635 640 Pro Ala Val Thr Glu Gln Glu Val Ala Gln Val Ala Ser Ala Ile Leu 645 650 655 Ser Leu Arg Arg Thr Leu Gln Gly Leu Gln Leu Asp Leu Pro Leu Glu 660 665 670 Glu Glu Thr Leu Ser Leu Pro Arg Asp Leu Glu Ser Leu Asp Arg Ser 675 680 685 Phe Asn Gly Leu Leu Thr Met Tyr Gln Arg Lys Arg Glu Gln Phe Glu 690 695 700 Lys Ile Ser Ser Ala Asp Pro Ser Gly Ala Phe Arg Met Leu Ser Thr 705 710 715 720 Ala Tyr Glu Gln Ser Ala Gln Ala Ala Gln Gln Val Ser Asp Ser Ser 725 730 735 Arg Leu Leu Asp Gln Leu Arg Asp Ser Arg Arg Glu Ala Glu Arg Leu 740 745 750 Val Arg Gln Ala Gly Gly Gly Gly Gly Thr Gly Ser Pro Lys Leu Val 755 760 765 Ala Leu Arg Leu Glu Met Ser Ser Leu Pro Asp Leu Thr Pro Thr Phe 770 775 780 Asn Lys Leu Cys Gly Asn Ser Arg Gln Met Ala Cys Thr Pro Ile Ser 785 790 795 800 Cys Pro Gly Glu Leu Cys Pro Gln Asp Asn Gly Thr Ala Cys Gly Ser 805 810 815 Arg Cys Arg Gly Val Leu Pro Arg Ala Gly Gly Ala Phe Leu Met Ala 820 825 830 Gly Gln Val Ala Glu Gln Leu Arg Gly Phe Asn Ala Gln Leu Gln Arg 835 840 845 Thr Arg Gln Met Ile Arg Ala Ala Glu Glu Ser Ala Ser Gln Ile Gln 850 855 860 Ser Ser Ala Gln Arg Leu Glu Thr Gln Val Ser Ala Ser Arg Ser Gln 865 870 875 880 Met Glu Glu Asp Val Arg Arg Thr Arg Leu Leu Ile Gln Gln Val Arg 885 890 895 Asp Phe Leu Thr Asp Pro Asp Thr Asp Ala Ala Thr Ile Gln Glu Val 900 905 910 Ser Glu Ala Val Leu Ala Leu Trp Leu Pro Thr Asp Ser Ala Thr Val 915 920 925 Leu Gln Lys Met Asn Glu Ile Gln Ala Ile Ala Ala Arg Leu Pro Asn 930 935 940 Val Asp Leu Val Leu Ser Gln Thr Lys Gln Asp Ile Ala Arg Ala Arg 945 950 955 960 Arg Leu Gln Ala Glu Ala Glu Glu Ala Arg Ser Arg Ala His Ala Val 965 970 975 Glu Gly Gln Val Glu Asp Val Val Gly Asn Leu Arg Gln Gly Thr Val 980 985 990 Ala Leu Gln Glu Ala Gln Asp Thr Met Gln Gly Thr Ser Arg Ser Leu 995 1000 1005 Arg Leu Ile Gln Asp Arg Val Ala Glu Val Gln Gln Val Leu Arg 1010 1015 1020 Pro Ala Glu Lys Leu Val Thr Ser Met Thr Lys Gln Leu Gly Asp 1025 1030 1035 Phe Trp Thr Arg Met Glu Glu Leu Arg His Gln Ala Arg Gln Gln 1040 1045 1050 Gly Ala Glu Ala Val Gln Ala Gln Gln Leu Ala Glu Gly Ala Ser 1055 1060 1065 Glu Gln Ala Leu Ser Ala Gln Glu Gly Phe Glu Arg Ile Lys Gln 1070 1075 1080 Lys Tyr Ala Glu Leu Lys Asp Arg Leu Gly Gln Ser Ser Met Leu 1085 1090 1095 Gly Glu Gln Gly Ala Arg Ile Gln Ser Val Lys Thr Glu Ala Glu 1100 1105 1110 Glu Leu Phe Gly Glu Thr Met Glu Met Met Asp Arg Met Lys Asp 1115 1120 1125 Met Glu Leu Glu Leu Leu Arg Gly Ser Gln Ala Ile Met Leu Arg 1130 1135 1140 Ser Ala Asp Leu Thr Gly Leu Glu Lys Arg Val Glu Gln Ile Arg 1145 1150 1155 Asp His Ile Asn Gly Arg Val Leu Tyr Tyr Ala Thr Cys Lys 1160 1165 1170 46623PRTHomo sapiens 46Met Ala Thr Glu His Val Asn Gly Asn Gly Thr Glu Glu Pro Met Asp 1 5 10 15 Thr Thr Ser Ala Val Ile His Ser Glu Asn Phe Gln Thr Leu Leu Asp 20 25 30 Ala Gly Leu Pro Gln Lys Val Ala Glu Lys Leu Asp Glu Ile Tyr Val 35 40 45 Ala Gly Leu Val Ala His Ser Asp Leu Asp Glu Arg Ala Ile Glu Ala 50 55 60 Leu Lys Glu Phe Asn Glu Asp Gly Ala Leu Ala Val Leu Gln Gln Phe 65 70 75 80 Lys Asp Ser Asp Leu Ser His Val Gln Asn Lys Ser Ala Phe Leu Cys 85 90 95 Gly Val Met Lys Thr Tyr Arg Gln Arg Glu Lys Gln Gly Thr Lys Val 100 105 110 Ala Asp Ser Ser Lys Gly Pro Asp Glu Ala Lys Ile Lys Ala Leu Leu 115 120 125 Glu Arg Thr Gly Tyr Thr Leu Asp Val Thr Thr Gly Gln Arg Lys Tyr 130 135 140 Gly Gly Pro Pro Pro Asp Ser Val Tyr Ser Gly Gln Gln Pro Ser Val 145 150 155 160 Gly Thr Glu Ile Phe Val Gly Lys Ile Pro Arg Asp Leu Phe Glu Asp 165 170 175 Glu Leu Val Pro Leu Phe Glu Lys Ala Gly Pro Ile Trp Asp Leu Arg 180 185 190 Leu Met Met Asp Pro Leu Thr Gly Leu Asn Arg Gly Tyr Ala Phe Val 195 200 205 Thr Phe Cys Thr Lys Glu Ala Ala Gln Glu Ala Val Lys Leu Tyr Asn 210 215 220 Asn His Glu Ile Arg Ser Gly Lys His Ile Gly Val Cys Ile Ser Val 225 230 235 240 Ala Asn Asn Arg Leu Phe Val Gly Ser Ile Pro Lys Ser Lys Thr Lys 245 250 255 Glu Gln Ile Leu Glu Glu Phe Ser Lys Val Thr Glu Gly Leu Thr Asp 260 265 270 Val Ile Leu Tyr His Gln Pro Asp Asp Lys Lys Lys Asn Arg Gly Phe 275 280 285 Cys Phe Leu Glu Tyr Glu Asp His Lys Thr Ala Ala Gln Ala Arg Arg 290 295 300 Arg Leu Met Ser Gly Lys Val Lys Val Trp Gly Asn Val Gly Thr Val 305 310 315 320 Glu Trp Ala Asp Pro Ile Glu Asp Pro Asp Pro Glu Val Met Ala Lys 325 330 335 Val Lys Val Leu Phe Val Arg Asn Leu Ala Asn Thr Val Thr Glu Glu 340 345 350 Ile Leu Glu Lys Ala Phe Ser Gln Phe Gly Lys Leu Glu Arg Val Lys 355 360 365 Lys Leu Lys Asp Tyr Ala Phe Ile His Phe Asp Glu Arg Asp Gly Ala 370 375 380 Val Lys Ala Met Glu Glu Met Asn Gly Lys Asp Leu Glu Gly Glu Asn 385 390 395 400 Ile Glu Ile Val Phe Ala Lys Pro Pro Asp Gln Lys Arg Lys Glu Arg 405 410 415 Lys Ala Gln Arg Gln Ala Ala Lys Asn Gln Met Tyr Asp Asp Tyr Tyr 420 425 430 Tyr Tyr Gly Pro Pro His Met Pro Pro Pro Thr Arg Gly Arg Gly Arg 435 440 445 Gly Gly Arg Gly Gly Tyr Gly Tyr Pro Pro Asp Tyr Tyr Gly Tyr Glu 450 455 460 Asp Tyr Tyr Asp Tyr Tyr Gly Tyr Asp Tyr His Asn Tyr Arg Gly Gly 465 470 475 480 Tyr Glu Asp Pro Tyr Tyr Gly Tyr Glu Asp Phe Gln Val Gly Ala Arg 485 490 495 Gly Arg Gly Gly Arg Gly Ala Arg Gly Ala Ala Pro Ser Arg Gly Arg 500 505 510 Gly Ala Ala Pro Pro Arg Gly Arg Ala Gly Tyr Ser Gln Arg Gly Gly 515 520 525 Pro Gly Ser Ala Arg Gly Val Arg Gly Ala Arg Gly Gly Ala Gln Gln 530 535 540 Gln Arg Gly Arg Gly Val Arg Gly Ala Arg Gly Gly Arg Gly Gly Asn 545 550 555 560 Val Gly Gly Lys Arg Lys Ala Asp Gly Tyr Asn Gln Pro Asp Ser Lys 565 570 575 Arg Arg Gln Thr Asn Asn Gln Asn Trp Gly Ser Gln Pro Ile Ala Gln 580 585 590 Gln Pro Leu Gln Gly Gly Asp His Ser Gly Asn Tyr Gly Tyr Lys Ser 595 600 605 Glu Asn Gln Glu Phe Tyr Gln Asp Thr Phe Gly Gln Gln Trp Lys 610 615 620 47147PRTHomo sapiens 47Met Gly His Phe Thr Glu Glu Asp Lys Ala Thr Ile Thr Ser Leu Trp 1 5 10 15 Gly Lys Val Asn Val Glu Asp Ala Gly Gly Glu Thr Leu Gly Arg Leu 20 25 30 Leu Val Val Tyr Pro Trp Thr Gln Arg Phe Phe Asp Ser Phe Gly Asn 35 40 45 Leu Ser Ser Ala Ser Ala Ile Met Gly Asn Pro Lys Val Lys Ala His 50 55 60 Gly Lys Lys Val Leu Thr Ser Leu Gly Asp Ala Ile Lys His Leu Asp 65 70 75 80 Asp Leu Lys Gly Thr Phe Ala Gln Leu Ser Glu Leu His Arg Asp Lys 85 90 95 Leu His Val Asp Pro Glu Asn Phe Lys Leu Leu Gly Asn Val Leu Val 100 105 110 Thr Val Leu Ala Ile His Phe Gly Lys Glu Phe Thr Pro Glu Val Gln 115 120 125 Ala Ser Trp Gln Lys Met Val Thr Gly Val Ala Ser Ala Leu Ser Ser 130 135 140 Arg Tyr His 145 48210PRTHomo sapiens 48Met Pro Pro Tyr Thr Val Val Tyr Phe Pro Val Arg Gly Arg Cys Ala 1 5 10 15 Ala Leu Arg Met Leu Leu Ala Asp Gln Gly Gln Ser Trp Lys Glu Glu 20 25 30 Val Val Thr Val Glu Thr Trp Gln Glu Gly Ser Leu Lys Ala Ser Cys 35 40 45 Leu Tyr Gly Gln Leu Pro Lys Phe Gln Asp Gly Asp Leu Thr Leu Tyr 50 55 60 Gln Ser Asn Thr Ile Leu Arg His Leu Gly Arg Thr Leu Gly Leu Tyr 65 70

75 80 Gly Lys Asp Gln Gln Glu Ala Ala Leu Val Asp Met Val Asn Asp Gly 85 90 95 Val Glu Asp Leu Arg Cys Lys Tyr Ile Ser Leu Ile Tyr Thr Asn Tyr 100 105 110 Glu Ala Gly Lys Asp Asp Tyr Val Lys Ala Leu Pro Gly Gln Leu Lys 115 120 125 Pro Phe Glu Thr Leu Leu Ser Gln Asn Gln Gly Gly Lys Thr Phe Ile 130 135 140 Val Gly Asp Gln Ile Ser Phe Ala Asp Tyr Asn Leu Leu Asp Leu Leu 145 150 155 160 Leu Ile His Glu Val Leu Ala Pro Gly Cys Leu Asp Ala Phe Pro Leu 165 170 175 Leu Ser Ala Tyr Val Gly Arg Leu Ser Ala Arg Pro Lys Leu Lys Ala 180 185 190 Phe Leu Ala Ser Pro Glu Tyr Val Asn Leu Pro Ile Asn Gly Asn Gly 195 200 205 Lys Gln 210 49364PRTHomo sapiens 49Met Pro Tyr Gln Tyr Pro Ala Leu Thr Pro Glu Gln Lys Lys Glu Leu 1 5 10 15 Ser Asp Ile Ala His Arg Ile Val Ala Pro Gly Lys Gly Ile Leu Ala 20 25 30 Ala Asp Glu Ser Thr Gly Ser Ile Ala Lys Arg Leu Gln Ser Ile Gly 35 40 45 Thr Glu Asn Thr Glu Glu Asn Arg Arg Phe Tyr Arg Gln Leu Leu Leu 50 55 60 Thr Ala Asp Asp Arg Val Asn Pro Cys Ile Gly Gly Val Ile Leu Phe 65 70 75 80 His Glu Thr Leu Tyr Gln Lys Ala Asp Asp Gly Arg Pro Phe Pro Gln 85 90 95 Val Ile Lys Ser Lys Gly Gly Val Val Gly Ile Lys Val Asp Lys Gly 100 105 110 Val Val Pro Leu Ala Gly Thr Asn Gly Glu Thr Thr Thr Gln Gly Leu 115 120 125 Asp Gly Leu Ser Glu Arg Cys Ala Gln Tyr Lys Lys Asp Gly Ala Asp 130 135 140 Phe Ala Lys Trp Arg Cys Val Leu Lys Ile Gly Glu His Thr Pro Ser 145 150 155 160 Ala Leu Ala Ile Met Glu Asn Ala Asn Val Leu Ala Arg Tyr Ala Ser 165 170 175 Ile Cys Gln Gln Asn Gly Ile Val Pro Ile Val Glu Pro Glu Ile Leu 180 185 190 Pro Asp Gly Asp His Asp Leu Lys Arg Cys Gln Tyr Val Thr Glu Lys 195 200 205 Val Leu Ala Ala Val Tyr Lys Ala Leu Ser Asp His His Ile Tyr Leu 210 215 220 Glu Gly Thr Leu Leu Lys Pro Asn Met Val Thr Pro Gly His Ala Cys 225 230 235 240 Thr Gln Lys Phe Ser His Glu Glu Ile Ala Met Ala Thr Val Thr Ala 245 250 255 Leu Arg Arg Thr Val Pro Pro Ala Val Thr Gly Ile Thr Phe Leu Ser 260 265 270 Gly Gly Gln Ser Glu Glu Glu Ala Ser Ile Asn Leu Asn Ala Ile Asn 275 280 285 Lys Cys Pro Leu Leu Lys Pro Trp Ala Leu Thr Phe Ser Tyr Gly Arg 290 295 300 Ala Leu Gln Ala Ser Ala Leu Lys Ala Trp Gly Gly Lys Lys Glu Asn 305 310 315 320 Leu Lys Ala Ala Gln Glu Glu Tyr Val Lys Arg Ala Leu Ala Asn Ser 325 330 335 Leu Ala Cys Gln Gly Lys Tyr Thr Pro Ser Gly Gln Ala Gly Ala Ala 340 345 350 Ala Ser Glu Ser Leu Phe Val Ser Asn His Ala Tyr 355 360 50188PRTHomo sapiens 50Met Gly Val Asp Ile Arg His Asn Lys Asp Arg Lys Val Arg Arg Lys 1 5 10 15 Glu Pro Lys Ser Gln Asp Ile Tyr Leu Arg Leu Leu Val Lys Leu Tyr 20 25 30 Arg Phe Leu Ala Arg Arg Thr Asn Ser Thr Phe Asn Gln Val Val Leu 35 40 45 Lys Arg Leu Phe Met Ser Arg Thr Asn Arg Pro Pro Leu Ser Leu Ser 50 55 60 Arg Met Ile Arg Lys Met Lys Leu Pro Gly Arg Glu Asn Lys Thr Ala 65 70 75 80 Val Val Val Gly Thr Ile Thr Asp Asp Val Arg Val Gln Glu Val Pro 85 90 95 Lys Leu Lys Val Cys Ala Leu Arg Val Thr Ser Arg Ala Arg Ser Arg 100 105 110 Ile Leu Arg Ala Gly Gly Lys Ile Leu Thr Phe Asp Gln Leu Ala Leu 115 120 125 Asp Ser Pro Lys Gly Cys Gly Thr Val Leu Leu Ser Gly Pro Arg Lys 130 135 140 Gly Arg Glu Val Tyr Arg His Phe Gly Lys Ala Pro Gly Thr Pro His 145 150 155 160 Ser His Thr Lys Pro Tyr Val Arg Ser Lys Gly Arg Lys Phe Glu Arg 165 170 175 Ala Arg Gly Arg Arg Ala Ser Arg Gly Tyr Lys Asn 180 185 51858PRTHomo sapiens 51Met Val Asn Phe Thr Val Asp Gln Ile Arg Ala Ile Met Asp Lys Lys 1 5 10 15 Ala Asn Ile Arg Asn Met Ser Val Ile Ala His Val Asp His Gly Lys 20 25 30 Ser Thr Leu Thr Asp Ser Leu Val Cys Lys Ala Gly Ile Ile Ala Ser 35 40 45 Ala Arg Ala Gly Glu Thr Arg Phe Thr Asp Thr Arg Lys Asp Glu Gln 50 55 60 Glu Arg Cys Ile Thr Ile Lys Ser Thr Ala Ile Ser Leu Phe Tyr Glu 65 70 75 80 Leu Ser Glu Asn Asp Leu Asn Phe Ile Lys Gln Ser Lys Asp Gly Ala 85 90 95 Gly Phe Leu Ile Asn Leu Ile Asp Ser Pro Gly His Val Asp Phe Ser 100 105 110 Ser Glu Val Thr Ala Ala Leu Arg Val Thr Asp Gly Ala Leu Val Val 115 120 125 Val Asp Cys Val Ser Gly Val Cys Val Gln Thr Glu Thr Val Leu Arg 130 135 140 Gln Ala Ile Ala Glu Arg Ile Lys Pro Val Leu Met Met Asn Lys Met 145 150 155 160 Asp Arg Ala Leu Leu Glu Leu Gln Leu Glu Pro Glu Glu Leu Tyr Gln 165 170 175 Thr Phe Gln Arg Ile Val Glu Asn Val Asn Val Ile Ile Ser Thr Tyr 180 185 190 Gly Glu Gly Glu Ser Gly Pro Met Gly Asn Ile Met Ile Asp Pro Val 195 200 205 Leu Gly Thr Val Gly Phe Gly Ser Gly Leu His Gly Trp Ala Phe Thr 210 215 220 Leu Lys Gln Phe Ala Glu Met Tyr Val Ala Lys Phe Ala Ala Lys Gly 225 230 235 240 Glu Gly Gln Leu Gly Pro Ala Glu Arg Ala Lys Lys Val Glu Asp Met 245 250 255 Met Lys Lys Leu Trp Gly Asp Arg Tyr Phe Asp Pro Ala Asn Gly Lys 260 265 270 Phe Ser Lys Ser Ala Thr Ser Pro Glu Gly Lys Lys Leu Pro Arg Thr 275 280 285 Phe Cys Gln Leu Ile Leu Asp Pro Ile Phe Lys Val Phe Asp Ala Ile 290 295 300 Met Asn Phe Lys Lys Glu Glu Thr Ala Lys Leu Ile Glu Lys Leu Asp 305 310 315 320 Ile Lys Leu Asp Ser Glu Asp Lys Asp Lys Glu Gly Lys Pro Leu Leu 325 330 335 Lys Ala Val Met Arg Arg Trp Leu Pro Ala Gly Asp Ala Leu Leu Gln 340 345 350 Met Ile Thr Ile His Leu Pro Ser Pro Val Thr Ala Gln Lys Tyr Arg 355 360 365 Cys Glu Leu Leu Tyr Glu Gly Pro Pro Asp Asp Glu Ala Ala Met Gly 370 375 380 Ile Lys Ser Cys Asp Pro Lys Gly Pro Leu Met Met Tyr Ile Ser Lys 385 390 395 400 Met Val Pro Thr Ser Asp Lys Gly Arg Phe Tyr Ala Phe Gly Arg Val 405 410 415 Phe Ser Gly Leu Val Ser Thr Gly Leu Lys Val Arg Ile Met Gly Pro 420 425 430 Asn Tyr Thr Pro Gly Lys Lys Glu Asp Leu Tyr Leu Lys Pro Ile Gln 435 440 445 Arg Thr Ile Leu Met Met Gly Arg Tyr Val Glu Pro Ile Glu Asp Val 450 455 460 Pro Cys Gly Asn Ile Val Gly Leu Val Gly Val Asp Gln Phe Leu Val 465 470 475 480 Lys Thr Gly Thr Ile Thr Thr Phe Glu His Ala His Asn Met Arg Val 485 490 495 Met Lys Phe Ser Val Ser Pro Val Val Arg Val Ala Val Glu Ala Lys 500 505 510 Asn Pro Ala Asp Leu Pro Lys Leu Val Glu Gly Leu Lys Arg Leu Ala 515 520 525 Lys Ser Asp Pro Met Val Gln Cys Ile Ile Glu Glu Ser Gly Glu His 530 535 540 Ile Ile Ala Gly Ala Gly Glu Leu His Leu Glu Ile Cys Leu Lys Asp 545 550 555 560 Leu Glu Glu Asp His Ala Cys Ile Pro Ile Lys Lys Ser Asp Pro Val 565 570 575 Val Ser Tyr Arg Glu Thr Val Ser Glu Glu Ser Asn Val Leu Cys Leu 580 585 590 Ser Lys Ser Pro Asn Lys His Asn Arg Leu Tyr Met Lys Ala Arg Pro 595 600 605 Phe Pro Asp Gly Leu Ala Glu Asp Ile Asp Lys Gly Glu Val Ser Ala 610 615 620 Arg Gln Glu Leu Lys Gln Arg Ala Arg Tyr Leu Ala Glu Lys Tyr Glu 625 630 635 640 Trp Asp Val Ala Glu Ala Arg Lys Ile Trp Cys Phe Gly Pro Asp Gly 645 650 655 Thr Gly Pro Asn Ile Leu Thr Asp Ile Thr Lys Gly Val Gln Tyr Leu 660 665 670 Asn Glu Ile Lys Asp Ser Val Val Ala Gly Phe Gln Trp Ala Thr Lys 675 680 685 Glu Gly Ala Leu Cys Glu Glu Asn Met Arg Gly Val Arg Phe Asp Val 690 695 700 His Asp Val Thr Leu His Ala Asp Ala Ile His Arg Gly Gly Gly Gln 705 710 715 720 Ile Ile Pro Thr Ala Arg Arg Cys Leu Tyr Ala Ser Val Leu Thr Ala 725 730 735 Gln Pro Arg Leu Met Glu Pro Ile Tyr Leu Val Glu Ile Gln Cys Pro 740 745 750 Glu Gln Val Val Gly Gly Ile Tyr Gly Val Leu Asn Arg Lys Arg Gly 755 760 765 His Val Phe Glu Glu Ser Gln Val Ala Gly Thr Pro Met Phe Val Val 770 775 780 Lys Ala Tyr Leu Pro Val Asn Glu Ser Phe Gly Phe Thr Ala Asp Leu 785 790 795 800 Arg Ser Asn Thr Gly Gly Gln Ala Phe Pro Gln Cys Val Phe Asp His 805 810 815 Trp Gln Ile Leu Pro Gly Asp Pro Phe Asp Asn Ser Ser Arg Pro Ser 820 825 830 Gln Val Val Ala Glu Thr Arg Lys Arg Lys Gly Leu Lys Glu Gly Ile 835 840 845 Pro Ala Leu Asp Asn Phe Leu Asp Lys Leu 850 855 52427PRTHomo sapiens 52Met Ala Cys Ala Arg Pro Leu Ile Ser Val Tyr Ser Glu Lys Gly Glu 1 5 10 15 Ser Ser Gly Lys Asn Val Thr Leu Pro Ala Val Phe Lys Ala Pro Ile 20 25 30 Arg Pro Asp Ile Val Asn Phe Val His Thr Asn Leu Arg Lys Asn Asn 35 40 45 Arg Gln Pro Tyr Ala Val Ser Glu Leu Ala Gly His Gln Thr Ser Ala 50 55 60 Glu Ser Trp Gly Thr Gly Arg Ala Val Ala Arg Ile Pro Arg Val Arg 65 70 75 80 Gly Gly Gly Thr His Arg Ser Gly Gln Gly Ala Phe Gly Asn Met Cys 85 90 95 Arg Gly Gly Arg Met Phe Ala Pro Thr Lys Thr Trp Arg Arg Trp His 100 105 110 Arg Arg Val Asn Thr Thr Gln Lys Arg Tyr Ala Ile Cys Ser Ala Leu 115 120 125 Ala Ala Ser Ala Leu Pro Ala Leu Val Met Ser Lys Gly His Arg Ile 130 135 140 Glu Glu Val Pro Glu Leu Pro Leu Val Val Glu Asp Lys Val Glu Gly 145 150 155 160 Tyr Lys Lys Thr Lys Glu Ala Val Leu Leu Leu Lys Lys Leu Lys Ala 165 170 175 Trp Asn Asp Ile Lys Lys Val Tyr Ala Ser Gln Arg Met Arg Ala Gly 180 185 190 Lys Gly Lys Met Arg Asn Arg Arg Arg Ile Gln Arg Arg Gly Pro Cys 195 200 205 Ile Ile Tyr Asn Glu Asp Asn Gly Ile Ile Lys Ala Phe Arg Asn Ile 210 215 220 Pro Gly Ile Thr Leu Leu Asn Val Ser Lys Leu Asn Ile Leu Lys Leu 225 230 235 240 Ala Pro Gly Gly His Val Gly Arg Phe Cys Ile Trp Thr Glu Ser Ala 245 250 255 Phe Arg Lys Leu Asp Glu Leu Tyr Gly Thr Trp Arg Lys Ala Ala Ser 260 265 270 Leu Lys Ser Asn Tyr Asn Leu Pro Met His Lys Met Ile Asn Thr Asp 275 280 285 Leu Ser Arg Ile Leu Lys Ser Pro Glu Ile Gln Arg Ala Leu Arg Ala 290 295 300 Pro Arg Lys Lys Ile His Arg Arg Val Leu Lys Lys Asn Pro Leu Lys 305 310 315 320 Asn Leu Arg Ile Met Leu Lys Leu Asn Pro Tyr Ala Lys Thr Met Arg 325 330 335 Arg Asn Thr Ile Leu Arg Gln Ala Arg Asn His Lys Leu Arg Val Asp 340 345 350 Lys Ala Ala Ala Ala Ala Ala Ala Leu Gln Ala Lys Ser Asp Glu Lys 355 360 365 Ala Ala Val Ala Gly Lys Lys Pro Val Val Gly Lys Lys Gly Lys Lys 370 375 380 Ala Ala Val Gly Val Lys Lys Gln Lys Lys Pro Leu Val Gly Lys Lys 385 390 395 400 Ala Ala Ala Thr Lys Lys Pro Ala Pro Glu Lys Lys Pro Ala Glu Lys 405 410 415 Lys Pro Thr Thr Glu Glu Lys Lys Pro Ala Ala 420 425 53288PRTHomo sapiens 53Met Ala Gly Glu Lys Val Glu Lys Pro Asp Thr Lys Glu Lys Lys Pro 1 5 10 15 Glu Ala Lys Lys Val Asp Ala Gly Gly Lys Val Lys Lys Gly Asn Leu 20 25 30 Lys Ala Lys Lys Pro Lys Lys Gly Lys Pro His Cys Ser Arg Asn Pro 35 40 45 Val Leu Val Arg Gly Ile Gly Arg Tyr Ser Arg Ser Ala Met Tyr Ser 50 55 60 Arg Lys Ala Met Tyr Lys Arg Lys Tyr Ser Ala Ala Lys Ser Lys Val 65 70 75 80 Glu Lys Lys Lys Lys Glu Lys Val Leu Ala Thr Val Thr Lys Pro Val 85 90 95 Gly Gly Asp Lys Asn Gly Gly Thr Arg Val Val Lys Leu Arg Lys Met 100 105 110 Pro Arg Tyr Tyr Pro Thr Glu Asp Val Pro Arg Lys Leu Leu Ser His 115 120 125 Gly Lys Lys Pro Phe Ser Gln His Val Arg Lys Leu Arg Ala Ser Ile 130 135 140 Thr Pro Gly Thr Ile Leu Ile Ile Leu Thr Gly Arg His Arg Gly Lys 145 150 155 160 Arg Val Val Phe Leu Lys Gln Leu Ala Ser Gly Leu Leu Leu Val Thr 165 170 175 Gly Pro Leu Val Leu Asn Arg Val Pro Leu Arg Arg Thr His Gln Lys 180 185 190 Phe Val Ile Ala Thr Ser Thr Lys Ile Asp Ile Ser Asn Val Lys Ile 195 200 205 Pro Lys His Leu Thr Asp Ala Tyr Phe Lys Lys Lys Lys Leu Arg Lys 210 215 220 Pro Arg His Gln Glu Gly Glu Ile Phe Asp Thr Glu Lys Glu Lys Tyr 225 230 235 240 Glu Ile Thr Glu Gln Arg Lys Ile Asp Gln Lys Ala Val Asp Ser Gln 245 250 255 Ile Leu Pro Lys Ile Lys Ala Ile Pro Gln Leu Gln Gly Tyr Leu Arg 260 265 270 Ser Val Phe Ala Leu Thr Asn Gly Ile Tyr Pro His Lys Leu Val Phe 275 280 285 54469PRTHomo sapiens 54Met Ser Ile His Phe Ser Ser Pro Val Phe Thr Ser Arg Ser Ala Ala 1 5 10 15 Phe Ser Gly Arg Gly Ala Gln Val Arg Leu Ser Ser Ala Arg Pro Gly 20 25

30 Gly Leu Gly Ser Ser Ser Leu Tyr Gly Leu Gly Ala Ser Arg Pro Arg 35 40 45 Val Ala Val Arg Ser Ala Tyr Gly Gly Pro Val Gly Ala Gly Ile Arg 50 55 60 Glu Val Thr Ile Asn Gln Ser Leu Leu Ala Pro Leu Arg Leu Asp Ala 65 70 75 80 Asp Pro Ser Leu Gln Arg Val Arg Gln Glu Glu Ser Glu Gln Ile Lys 85 90 95 Thr Leu Asn Asn Lys Phe Ala Ser Phe Ile Asp Lys Val Arg Phe Leu 100 105 110 Glu Gln Gln Asn Lys Leu Leu Glu Thr Lys Trp Thr Leu Leu Gln Glu 115 120 125 Gln Lys Ser Ala Lys Ser Ser Arg Leu Pro Asp Ile Phe Glu Ala Gln 130 135 140 Ile Ala Gly Leu Arg Gly Gln Leu Glu Ala Leu Gln Val Asp Gly Gly 145 150 155 160 Arg Leu Glu Ala Glu Leu Arg Ser Met Gln Asp Val Val Glu Asp Phe 165 170 175 Lys Asn Lys Tyr Glu Asp Glu Ile Asn His Arg Thr Ala Ala Glu Asn 180 185 190 Glu Phe Val Val Leu Lys Lys Asp Val Asp Ala Ala Tyr Met Ser Lys 195 200 205 Val Glu Leu Glu Ala Lys Val Asp Ala Leu Asn Asp Glu Ile Asn Phe 210 215 220 Leu Arg Thr Leu Asn Glu Thr Glu Leu Thr Glu Leu Gln Ser Gln Ile 225 230 235 240 Ser Asp Thr Ser Val Val Leu Ser Met Asp Asn Ser Arg Ser Leu Asp 245 250 255 Leu Asp Gly Ile Ile Ala Glu Val Lys Ala Gln Tyr Glu Glu Met Ala 260 265 270 Lys Cys Ser Arg Ala Glu Ala Glu Ala Trp Tyr Gln Thr Lys Phe Glu 275 280 285 Thr Leu Gln Ala Gln Ala Gly Lys His Gly Asp Asp Leu Arg Asn Thr 290 295 300 Arg Asn Glu Ile Ser Glu Met Asn Arg Ala Ile Gln Arg Leu Gln Ala 305 310 315 320 Glu Ile Asp Asn Ile Lys Asn Gln Arg Ala Lys Leu Glu Ala Ala Ile 325 330 335 Ala Glu Ala Glu Glu Arg Gly Glu Leu Ala Leu Lys Asp Ala Arg Ala 340 345 350 Lys Gln Glu Glu Leu Glu Ala Ala Leu Gln Arg Gly Lys Gln Asp Met 355 360 365 Ala Arg Gln Leu Arg Glu Tyr Gln Glu Leu Met Ser Val Lys Leu Ala 370 375 380 Leu Asp Ile Glu Ile Ala Thr Tyr Arg Lys Leu Leu Glu Gly Glu Glu 385 390 395 400 Ser Arg Leu Ala Gly Asp Gly Val Gly Ala Val Asn Ile Ser Val Met 405 410 415 Asn Ser Thr Gly Gly Ser Ser Ser Gly Gly Gly Ile Gly Leu Thr Leu 420 425 430 Gly Gly Thr Met Gly Ser Asn Ala Leu Ser Phe Ser Ser Ser Ala Gly 435 440 445 Pro Gly Leu Leu Lys Ala Tyr Ser Ile Arg Thr Ala Ser Ala Ser Arg 450 455 460 Arg Ser Ala Arg Asp 465 55353PRTHomo sapiens 55Met Glu Lys Thr Leu Glu Thr Val Pro Leu Glu Arg Lys Lys Arg Glu 1 5 10 15 Lys Glu Gln Phe Arg Lys Leu Phe Ile Gly Gly Leu Ser Phe Glu Thr 20 25 30 Thr Glu Glu Ser Leu Arg Asn Tyr Tyr Glu Gln Trp Gly Lys Leu Thr 35 40 45 Asp Cys Val Val Met Arg Asp Pro Ala Ser Lys Arg Ser Arg Gly Phe 50 55 60 Gly Phe Val Thr Phe Ser Ser Met Ala Glu Val Asp Ala Ala Met Ala 65 70 75 80 Ala Arg Pro His Ser Ile Asp Gly Arg Val Val Glu Pro Lys Arg Ala 85 90 95 Val Ala Arg Glu Glu Ser Gly Lys Pro Gly Ala His Val Thr Val Lys 100 105 110 Lys Leu Phe Val Gly Gly Ile Lys Glu Asp Thr Glu Glu His His Leu 115 120 125 Arg Asp Tyr Phe Glu Glu Tyr Gly Lys Ile Asp Thr Ile Glu Ile Ile 130 135 140 Thr Asp Arg Gln Ser Gly Lys Lys Arg Gly Phe Gly Phe Val Thr Phe 145 150 155 160 Asp Asp His Asp Pro Val Asp Lys Ile Val Leu Gln Lys Tyr His Thr 165 170 175 Ile Asn Gly His Asn Ala Glu Val Arg Lys Ala Leu Ser Arg Gln Glu 180 185 190 Met Gln Glu Val Gln Ser Ser Arg Ser Gly Arg Gly Gly Asn Phe Gly 195 200 205 Phe Gly Asp Ser Arg Gly Gly Gly Gly Asn Phe Gly Pro Gly Pro Gly 210 215 220 Ser Asn Phe Arg Gly Gly Ser Asp Gly Tyr Gly Ser Gly Arg Gly Phe 225 230 235 240 Gly Asp Gly Tyr Asn Gly Tyr Gly Gly Gly Pro Gly Gly Gly Asn Phe 245 250 255 Gly Gly Ser Pro Gly Tyr Gly Gly Gly Arg Gly Gly Tyr Gly Gly Gly 260 265 270 Gly Pro Gly Tyr Gly Asn Gln Gly Gly Gly Tyr Gly Gly Gly Tyr Asp 275 280 285 Asn Tyr Gly Gly Gly Asn Tyr Gly Ser Gly Asn Tyr Asn Asp Phe Gly 290 295 300 Asn Tyr Asn Gln Gln Pro Ser Asn Tyr Gly Pro Met Lys Ser Gly Asn 305 310 315 320 Phe Gly Gly Ser Arg Asn Met Gly Gly Pro Tyr Gly Gly Gly Asn Tyr 325 330 335 Gly Pro Gly Gly Ser Gly Gly Ser Gly Gly Tyr Gly Gly Arg Ser Arg 340 345 350 Tyr 5690PRTHomo sapiens 56Met Ala Cys Pro Leu Asp Gln Ala Ile Gly Leu Leu Val Ala Ile Phe 1 5 10 15 His Lys Tyr Ser Gly Arg Glu Gly Asp Lys His Thr Leu Ser Lys Lys 20 25 30 Glu Leu Lys Glu Leu Ile Gln Lys Glu Leu Thr Ile Gly Ser Lys Leu 35 40 45 Gln Asp Ala Glu Ile Ala Arg Leu Met Glu Asp Leu Asp Arg Asn Lys 50 55 60 Asp Gln Glu Val Asn Phe Gln Glu Tyr Val Thr Phe Leu Gly Ala Leu 65 70 75 80 Ala Leu Ile Tyr Asn Glu Ala Leu Lys Gly 85 90 572096PRTHomo sapiens 57Met Cys Ser Thr Pro Gly Met Pro Ala Pro Gly Ala Ser Leu Ala Leu 1 5 10 15 Arg Val Ser Phe Val Asp Val His Pro Asp Val Ile Pro Val Gln Leu 20 25 30 Trp Gly Leu Val Gly Glu Arg Arg Gly Glu Tyr Leu Arg Leu Ser Arg 35 40 45 Glu Ile Gln Glu Ala Ala Ala Thr Arg Gly Gln Trp Ala Leu Gly Ser 50 55 60 Ala Ser Ala Ser Pro Gly Glu Leu Cys Leu Val Gln Val Gly Leu Leu 65 70 75 80 Trp His Arg Cys Arg Val Val Ser Arg Gln Ala Gln Glu Ser Arg Val 85 90 95 Phe Leu Leu Asp Glu Gly Arg Thr Ile Thr Ala Gly Ala Gly Ser Leu 100 105 110 Ala Pro Gly Arg Arg Glu Phe Phe Asn Leu Pro Ser Glu Val Leu Gly 115 120 125 Cys Val Leu Ala Gly Leu Val Pro Ala Gly Cys Gly Ala Gly Ser Gly 130 135 140 Glu Pro Pro Gln His Trp Pro Ala Asp Ala Val Asp Phe Leu Ser Asn 145 150 155 160 Leu Gln Gly Lys Glu Val His Gly Cys Val Leu Asp Val Leu Leu Leu 165 170 175 His Arg Leu Val Leu Leu Glu Val Pro Asp Val Phe Gln Gln Met Arg 180 185 190 Glu Leu Gly Leu Ala Arg Arg Val Pro Asp Ser Leu Phe Arg Ser Leu 195 200 205 Leu Glu Arg Tyr Leu Thr Ala Ala Thr Ala Ser Val Gly Ser Gly Val 210 215 220 Pro Val Leu Ser Arg Val Pro Leu Lys Gln Lys Gln Pro Gly Leu Asp 225 230 235 240 Tyr Phe Tyr Pro Gln Leu Gln Leu Gly Val Thr Glu Ala Val Val Ile 245 250 255 Thr Gln Val Cys His Pro His Arg Ile His Cys Gln Leu Arg Ser Val 260 265 270 Ser Gln Glu Ile His Arg Leu Ser Glu Ser Met Ala Gln Val Tyr Arg 275 280 285 Gly Ser Thr Gly Thr Gly Asp Glu Asn Ser Thr Ser Ala Thr Trp Glu 290 295 300 Glu Arg Glu Glu Ser Pro Asp Lys Pro Gly Ser Pro Cys Ala Ser Cys 305 310 315 320 Gly Leu Asp Gly His Trp Tyr Arg Ala Leu Leu Leu Glu Thr Phe Arg 325 330 335 Pro Gln Arg Cys Ala Gln Val Leu His Val Asp Tyr Gly Arg Lys Glu 340 345 350 Leu Val Ser Cys Ser Ser Leu Arg Tyr Leu Leu Pro Glu Tyr Phe Arg 355 360 365 Met Pro Val Val Thr Tyr Pro Cys Ala Leu Tyr Gly Leu Trp Asp Gly 370 375 380 Gly Arg Gly Trp Ser Arg Ser Gln Val Gly Asp Leu Lys Thr Leu Ile 385 390 395 400 Leu Gly Lys Ala Val Asn Ala Lys Ile Glu Phe Tyr Cys Ser Phe Glu 405 410 415 His Val Tyr Tyr Val Ser Leu Tyr Gly Glu Asp Gly Ile Asn Leu Asn 420 425 430 Arg Val Phe Gly Val Gln Ser Cys Cys Leu Ala Asp Arg Val Leu Gln 435 440 445 Ser Gln Ala Thr Glu Glu Glu Glu Pro Glu Thr Ser Gln Ser Gln Ser 450 455 460 Pro Ala Glu Glu Val Asp Glu Glu Ile Ser Leu Pro Ala Leu Arg Ser 465 470 475 480 Ile Arg Leu Lys Met Asn Ala Phe Tyr Asp Ala Gln Val Glu Phe Val 485 490 495 Lys Asn Pro Ser Glu Phe Trp Ile Arg Leu Arg Lys His Asn Val Thr 500 505 510 Phe Ser Lys Leu Met Arg Arg Met Cys Gly Phe Tyr Ser Ser Ala Ser 515 520 525 Lys Leu Asp Gly Val Val Leu Lys Pro Glu Pro Asp Asp Leu Cys Cys 530 535 540 Val Lys Trp Lys Glu Asn Gly Tyr Tyr Arg Ala Ile Val Thr Lys Leu 545 550 555 560 Asp Asp Lys Ser Val Asp Val Phe Leu Val Asp Arg Gly Asn Ser Glu 565 570 575 Asn Val Asp Trp Tyr Asp Val Arg Met Leu Leu Pro Gln Phe Arg Gln 580 585 590 Leu Pro Ile Leu Ala Val Lys Cys Thr Leu Ala Asp Ile Trp Pro Leu 595 600 605 Gly Lys Thr Trp Ser Gln Glu Ala Val Ser Phe Phe Lys Lys Thr Val 610 615 620 Leu His Lys Glu Leu Val Ile His Ile Leu Asp Lys Gln Asp His Gln 625 630 635 640 Tyr Val Ile Glu Ile Leu Asp Glu Ser Arg Thr Gly Glu Glu Asn Ile 645 650 655 Ser Lys Val Ile Ala Gln Ala Gly Tyr Ala Lys Tyr Gln Glu Phe Glu 660 665 670 Thr Lys Glu Asn Ile Leu Val Asn Ala His Ser Pro Gly His Val Ser 675 680 685 Asn His Phe Thr Thr Glu Ser Asn Lys Ile Pro Phe Ala Lys Thr Gly 690 695 700 Glu Gly Glu Gln Lys Ala Lys Arg Glu Asn Lys Thr Thr Ser Val Ser 705 710 715 720 Lys Ala Leu Ser Asp Thr Thr Val Val Thr Asn Gly Ser Thr Glu Leu 725 730 735 Val Val Gln Glu Lys Val Lys Arg Ala Ser Val Tyr Phe Pro Leu Met 740 745 750 Gln Asn Cys Leu Glu Ile Lys Pro Gly Ser Ser Ser Lys Gly Glu Leu 755 760 765 Glu Val Gly Ser Thr Val Glu Val Arg Val Ser Tyr Val Glu Asn Pro 770 775 780 Gly Tyr Phe Trp Cys Gln Leu Thr Arg Asn Ile Gln Gly Leu Lys Thr 785 790 795 800 Leu Met Ser Asp Ile Gln Tyr Tyr Cys Lys Asn Thr Ala Ala Pro His 805 810 815 Gln Arg Asn Thr Leu Ala Cys Leu Ala Lys Arg Thr Val Asn Arg Gln 820 825 830 Trp Ser Arg Ala Leu Ile Ser Gly Ile Gln Ser Val Glu His Val Asn 835 840 845 Val Thr Phe Val Asp Tyr Gly Asp Arg Glu Met Val Ser Val Lys Asn 850 855 860 Ile Tyr Ser Ile Ser Glu Glu Phe Leu Lys Val Lys Ala Gln Ala Phe 865 870 875 880 Arg Cys Ser Leu Tyr Asn Leu Ile Gln Pro Val Gly Gln Asn Pro Phe 885 890 895 Val Trp Asp Val Lys Ala Ile Gln Ala Phe Asn Glu Phe Ile Asp Asn 900 905 910 Ala Trp Gln Lys Asn Leu Glu Leu Lys Cys Thr Ile Phe Ala Leu Ala 915 920 925 Ser Ile Asn Glu Glu Leu Phe Asn Ile Val Asp Leu Leu Thr Pro Phe 930 935 940 Gln Ser Ala Cys His Phe Leu Val Glu Lys Arg Leu Ala Arg Pro Val 945 950 955 960 Lys Leu Gln Lys Pro Leu Glu Ser Ser Val Gln Leu His Ser Tyr Phe 965 970 975 Tyr Ser Thr His Asp Met Lys Ile Gly Ser Glu Glu Leu Val Tyr Ile 980 985 990 Thr His Ile Asp Asp Pro Trp Thr Phe Tyr Cys Gln Leu Ala Arg Asn 995 1000 1005 Ala Asn Ile Leu Glu Gln Leu Ser Cys Ser Ile Thr Gln Leu Ser 1010 1015 1020 Lys Val Leu Leu Asn Leu Lys Thr Ser Pro Leu Asn Pro Gly Thr 1025 1030 1035 Leu Cys Leu Ala Lys Tyr Thr Asp Gly Asn Trp Tyr Arg Gly Ile 1040 1045 1050 Val Ile Glu Lys Glu Pro Lys Lys Val Phe Phe Val Asp Phe Gly 1055 1060 1065 Asn Ile Tyr Val Val Thr Ser Asp Asp Leu Leu Pro Ile Pro Ser 1070 1075 1080 Asp Ala Tyr Asp Val Leu Leu Leu Pro Met Gln Ala Val Arg Cys 1085 1090 1095 Ser Leu Ser Asp Ile Pro Asp His Ile Pro Glu Glu Val Val Val 1100 1105 1110 Trp Phe Gln Glu Thr Ile Leu Asp Lys Ser Leu Lys Ala Leu Val 1115 1120 1125 Val Ala Lys Asp Pro Asp Gly Thr Leu Ile Ile Glu Leu Tyr Gly 1130 1135 1140 Asp Asn Ile Gln Ile Ser Ala Ser Ile Asn Lys Lys Leu Gly Leu 1145 1150 1155 Leu Ser Tyr Lys Asp Arg Ile Arg Lys Lys Glu Ser Glu Val Leu 1160 1165 1170 Cys Ser Thr Thr Glu Thr Leu Glu Glu Lys Asn Glu Asn Met Lys 1175 1180 1185 Leu Pro Cys Thr Glu Tyr Leu Ser Lys Ser Val Gly Tyr Lys Leu 1190 1195 1200 Pro Asn Lys Glu Ile Leu Glu Glu Ser Tyr Lys Pro Gln Ile Asn 1205 1210 1215 Ser Ser Tyr Lys Glu Leu Lys Leu Leu Gln Ser Leu Thr Lys Thr 1220 1225 1230 Asn Leu Val Thr Gln Tyr Gln Asp Ser Val Gly Asn Lys Asn Ser 1235 1240 1245 Gln Val Phe Pro Leu Thr Thr Glu Lys Lys Glu Glu Ile Ser Ala 1250 1255 1260 Glu Thr Pro Leu Lys Thr Ala Arg Val Glu Ala Thr Leu Ser Glu 1265 1270 1275 Arg Lys Ile Gly Asp Ser Cys Asp Lys Asp Leu Pro Leu Lys Phe 1280 1285 1290 Cys Glu Phe Pro Gln Lys Thr Ile Met Pro Gly Phe Lys Thr Thr 1295 1300 1305 Val Tyr Val Ser His Ile Asn Asp Leu Ser Asp Phe Tyr Val Gln 1310 1315 1320 Leu Ile Glu Asp Glu Ala Glu Ile Ser His Leu Ser Glu Arg Leu 1325 1330 1335 Asn Ser Val Lys Thr Arg Pro Glu Tyr Tyr Val Gly Pro Pro Leu 1340 1345 1350 Gln Arg Gly Asp Met Ile Cys Ala Val Phe Pro Glu Asp Asn Leu 1355 1360 1365 Trp Tyr Arg Ala Val Ile Lys Glu Gln Gln Pro Asn Asp Leu Leu 1370 1375 1380 Ser Val Gln Phe Ile Asp Tyr Gly Asn Val Ser Val Val His Thr 1385 1390

1395 Asn Lys Ile Gly Arg Leu Asp Leu Val Asn Ala Ile Leu Pro Gly 1400 1405 1410 Leu Cys Ile His Cys Ser Leu Gln Gly Phe Glu Val Pro Asp Asn 1415 1420 1425 Lys Asn Ser Lys Lys Met Met His Tyr Phe Ser Gln Arg Thr Ser 1430 1435 1440 Glu Ala Ala Ile Arg Cys Glu Phe Val Lys Phe Gln Asp Arg Trp 1445 1450 1455 Glu Val Ile Leu Ala Asp Glu His Gly Ile Ile Ala Asp Asp Met 1460 1465 1470 Ile Ser Arg Tyr Ala Leu Ser Glu Lys Ser Gln Val Glu Leu Ser 1475 1480 1485 Thr Gln Val Ile Lys Ser Ala Ser Ser Lys Ser Val Asn Lys Ser 1490 1495 1500 Asp Ile Asp Thr Ser Val Phe Leu Asn Trp Tyr Asn Pro Glu Lys 1505 1510 1515 Lys Met Ile Arg Ala Tyr Ala Thr Val Ile Asp Gly Pro Glu Tyr 1520 1525 1530 Phe Trp Cys Gln Phe Ala Asp Thr Glu Lys Leu Gln Cys Leu Glu 1535 1540 1545 Val Glu Val Gln Thr Ala Gly Glu Gln Val Ala Asp Arg Arg Asn 1550 1555 1560 Cys Ile Pro Cys Pro Tyr Ile Gly Asp Pro Cys Ile Val Arg Tyr 1565 1570 1575 Arg Glu Asp Gly His Tyr Tyr Arg Ala Leu Ile Thr Asn Ile Cys 1580 1585 1590 Glu Asp Tyr Leu Val Ser Val Arg Leu Val Asp Phe Gly Asn Ile 1595 1600 1605 Glu Asp Cys Val Asp Pro Lys Ala Leu Trp Ala Ile Pro Ser Glu 1610 1615 1620 Leu Leu Ser Val Pro Met Gln Ala Phe Pro Cys Cys Leu Ser Gly 1625 1630 1635 Phe Asn Ile Ser Glu Gly Leu Cys Ser Gln Glu Gly Asn Asp Tyr 1640 1645 1650 Phe Tyr Glu Ile Ile Thr Glu Asp Val Leu Glu Ile Thr Ile Leu 1655 1660 1665 Glu Ile Arg Arg Asp Val Cys Asp Ile Pro Leu Ala Ile Val Asp 1670 1675 1680 Leu Lys Ser Lys Gly Lys Ser Ile Asn Glu Lys Met Glu Lys Tyr 1685 1690 1695 Ser Lys Thr Gly Ile Lys Ser Ala Leu Pro Tyr Glu Asn Ile Asp 1700 1705 1710 Ser Glu Ile Lys Gln Thr Leu Gly Ser Tyr Asn Leu Asp Val Gly 1715 1720 1725 Leu Lys Lys Leu Ser Asn Lys Ala Val Gln Asn Lys Ile Tyr Met 1730 1735 1740 Glu Gln Gln Thr Asp Glu Leu Ala Glu Ile Thr Glu Lys Asp Val 1745 1750 1755 Asn Ile Ile Gly Thr Lys Pro Ser Asn Phe Arg Asp Pro Lys Thr 1760 1765 1770 Asp Asn Ile Cys Glu Gly Phe Glu Asn Pro Cys Lys Asp Lys Ile 1775 1780 1785 Asp Thr Glu Glu Leu Glu Gly Glu Leu Glu Cys His Leu Val Asp 1790 1795 1800 Lys Ala Glu Phe Asp Asp Lys Tyr Leu Ile Thr Gly Phe Asn Thr 1805 1810 1815 Leu Leu Pro His Ala Asn Glu Thr Lys Glu Ile Leu Glu Leu Asn 1820 1825 1830 Ser Leu Glu Val Pro Leu Ser Pro Asp Asp Glu Ser Lys Glu Phe 1835 1840 1845 Leu Glu Leu Glu Ser Ile Glu Leu Gln Asn Ser Leu Val Val Asp 1850 1855 1860 Glu Glu Lys Gly Glu Leu Ser Pro Val Pro Pro Asn Val Pro Leu 1865 1870 1875 Ser Gln Glu Cys Val Thr Lys Gly Ala Met Glu Leu Phe Thr Leu 1880 1885 1890 Gln Leu Pro Leu Ser Cys Glu Ala Glu Lys Gln Pro Glu Leu Glu 1895 1900 1905 Leu Pro Thr Ala Gln Leu Pro Leu Asp Asp Lys Met Asp Pro Leu 1910 1915 1920 Ser Leu Gly Val Ser Gln Lys Ala Gln Glu Ser Met Cys Thr Glu 1925 1930 1935 Asp Met Arg Lys Ser Ser Cys Val Glu Ser Phe Asp Asp Gln Arg 1940 1945 1950 Arg Met Ser Leu His Leu His Gly Ala Asp Cys Asp Pro Lys Thr 1955 1960 1965 Gln Asn Glu Met Asn Ile Cys Glu Glu Glu Phe Val Glu Tyr Lys 1970 1975 1980 Asn Arg Asp Ala Ile Ser Ala Leu Met Pro Leu Phe Ser Glu Glu 1985 1990 1995 Glu Ser Ser Asp Gly Ser Lys His Asn Asn Gly Leu Pro Asp His 2000 2005 2010 Ile Ser Ala Gln Leu Gln Asn Thr Tyr Thr Leu Lys Ala Phe Thr 2015 2020 2025 Val Gly Ser Lys Cys Val Val Trp Ser Ser Leu Arg Asn Thr Trp 2030 2035 2040 Ser Lys Cys Glu Ile Leu Glu Thr Ala Glu Glu Gly Thr Arg Val 2045 2050 2055 Leu Asn Leu Ser Asn Gly Met Glu Glu Ile Val Asn Pro Glu Asn 2060 2065 2070 Val Trp Asn Gly Ile Pro Lys Leu Asp Lys Ser Pro Pro Glu Lys 2075 2080 2085 Arg Gly Leu Glu Val Met Glu Ile 2090 2095 58936PRTHomo sapiens 58Met Leu Leu Ala Pro Gln Gly Arg Ser Phe Ser Lys Lys Arg Met Gly 1 5 10 15 Leu Asn Arg Trp Lys Arg Phe Thr Arg Lys Pro Ser Pro Lys Pro Thr 20 25 30 Phe Gly Pro Asp Ser Val Glu His Trp Ile Lys Arg Val Glu Lys Ala 35 40 45 Ser Glu Phe Ala Val Ser Asn Ala Phe Phe Thr Arg Asn Ser Asp Leu 50 55 60 Pro Arg Ser Pro Trp Gly Gln Ile Thr Asp Leu Lys Thr Ser Glu Gln 65 70 75 80 Ile Glu Asp His Asp Glu Ile Tyr Ala Glu Ala Gln Glu Leu Val Asn 85 90 95 Asp Trp Leu Asp Thr Lys Leu Lys Gln Glu Leu Ala Ser Glu Glu Glu 100 105 110 Gly Asp Ala Lys Asn Thr Val Ser Ser Val Thr Ile Met Pro Glu Ala 115 120 125 Asn Gly His Leu Lys Tyr Asp Lys Phe Asp Asp Leu Cys Gly Tyr Leu 130 135 140 Glu Glu Glu Glu Glu Ser Thr Thr Val Gln Lys Phe Ile Asp His Leu 145 150 155 160 Leu His Lys Asn Val Val Asp Ser Ala Met Met Glu Asp Leu Gly Arg 165 170 175 Lys Glu Asn Gln Asp Lys Lys Gln Gln Lys Asp Pro Arg Leu Thr Met 180 185 190 Glu Met Arg His Lys Gln Val Lys Glu Asn Arg Leu Arg Arg Glu Lys 195 200 205 Glu Leu Glu Tyr Gln Arg Ile Glu Lys Thr Leu Lys Lys Ser Ala Phe 210 215 220 Leu Glu Ala Gln Cys Leu Val Gln Glu Glu Lys Lys Arg Lys Ala Leu 225 230 235 240 Glu Ala Lys Lys Glu Glu Glu Glu Ile Gln Arg Glu Met Val Lys Leu 245 250 255 Arg Arg Glu Ile Ile Glu Arg Arg Arg Thr Val Lys Ala Ala Trp Lys 260 265 270 Ile Glu Lys Lys Arg Gln Glu Glu Asn Ser Gln Asn Ser Ser Glu Lys 275 280 285 Val Met Phe Gln Ser Thr His Ile Leu Pro Asp Glu Glu Lys Met Val 290 295 300 Lys Glu Arg Lys Arg Lys Leu Lys Glu Val Leu Ile Gln Thr Phe Lys 305 310 315 320 Glu Asn Gln Gln Cys Gln Lys Arg Tyr Phe Ala Ala Trp His Lys Leu 325 330 335 Ile Leu Asp His Arg Ile Lys Leu Gly Lys Ala Gly Thr Leu Ser Asp 340 345 350 Trp Lys Ile Gln Leu Lys Val Leu Arg Ala Trp Arg Asp Tyr Thr Arg 355 360 365 Phe Gln Lys Leu Glu Arg Glu Thr Gln Ala Leu Glu Asn Asp Leu Arg 370 375 380 Glu Glu Asn Arg Lys Gln Gln Leu Ala Thr Glu Tyr Asn Arg Lys Gln 385 390 395 400 Val Leu Arg His Cys Phe Thr Glu Trp Gln His Trp His Gly Ala Glu 405 410 415 Leu Leu Lys Arg Glu Leu Ala Leu Thr Lys Glu Glu Thr Arg Lys Lys 420 425 430 Met Asp Ala Leu Leu Gln Ala Ala Ser Leu Gly Lys Leu Ser Ala Asn 435 440 445 Gly Leu Ser Gly Ile Ser Leu Pro Glu Glu Ala Thr Ala Met Val Gly 450 455 460 Pro Pro Val Lys Asn Gly Gln Glu Thr Ala Val Pro Pro Leu Trp Glu 465 470 475 480 Lys Pro Pro Leu Gly Ser Ser Gly Cys Met Leu Ser Pro Pro Leu Gly 485 490 495 Arg Thr Thr Thr Gly Asn Leu Gln Gly Ser Leu Gln Asn Val Ser Leu 500 505 510 Ser Ala Pro Gly Asn Lys Gln His Lys Thr Leu Gly Ala Glu Pro Ser 515 520 525 Gln Gln Pro Gly Ser Asn Glu Thr Leu Arg Thr Thr Ser Gln Lys Ala 530 535 540 Glu Pro Leu Cys Leu Gly His Phe His Asn Arg His Val Phe Gln Gln 545 550 555 560 Gln Leu Ile Glu Lys Gln Lys Lys Lys Leu Gln Glu Gln Gln Lys Thr 565 570 575 Ile Leu Glu Leu Lys Lys Asn Leu Gln Leu Ala Glu Ala Gln Trp Ala 580 585 590 Ala Glu His Ala Leu Ala Val Thr Glu Ala Gln Ser His Leu Leu Ser 595 600 605 Lys Pro Arg Glu Glu Glu Pro Arg Thr Cys Gln Met Leu Val Asn Ser 610 615 620 Pro Val Ala Ser Pro Gly Thr Glu Gly Arg Ser Asp Ser Arg Asn Ser 625 630 635 640 Leu Ser Gly Leu Arg Arg Lys Pro Lys Gln Leu Met Thr Pro His Pro 645 650 655 Ile Leu Lys Ala Met Glu Glu Arg Ala Ile Gln Arg Ala Glu Cys Arg 660 665 670 Arg Ile Leu Ala Glu Lys Lys Lys Lys Gln Glu Glu Glu Lys Leu Ala 675 680 685 Gln Leu Lys Ala Gln Glu Glu Glu Arg Gln Lys Arg Glu Ala Glu Glu 690 695 700 Lys Glu Ala Gln Leu Glu Arg Lys Arg Glu Glu Lys Arg Leu Lys Lys 705 710 715 720 Met Lys Glu Leu Glu Lys Gln Lys Arg Ile Lys Arg Asn Gln Gln Leu 725 730 735 Glu Ala Ile Ala Lys Glu His Tyr Glu Arg Val Leu Leu Arg Lys Lys 740 745 750 Gly Leu Glu Pro Trp Lys Arg Leu Arg Met Gln Ser Lys Gln Asn Ile 755 760 765 Gln Val Ala Glu Glu His Tyr Ser Leu Phe Leu Gln Arg Lys Tyr Met 770 775 780 Leu Thr Trp Phe Gln Arg Ser Gln Glu Ser Leu Ala Arg Lys Met Ala 785 790 795 800 Gln Ala Asp Gln Phe Tyr Ser Gln Ile Leu Leu Lys Arg Val Ile Gln 805 810 815 Ser Trp Leu Gln Tyr Val Ile Asp Leu Gln Glu Glu Val Arg Lys Phe 820 825 830 Cys Val His Phe Leu Gln Lys Lys Ile Phe Arg Ala Trp Phe Asn Met 835 840 845 Val Arg Glu Val Lys Ile Asp Ser Gln Gly Lys His Glu Ile Ala Ala 850 855 860 Glu His Ser Asp Arg Arg Ile Leu Trp Ile Thr Leu Arg Thr Trp Lys 865 870 875 880 Lys Phe Val Lys Phe Met Lys Glu Glu Arg Val Lys Glu Glu Arg Arg 885 890 895 Gln Gln Leu Arg Arg Lys Val Val Glu Ile Leu Pro Asp Phe Gln Val 900 905 910 Pro Gly Arg Tyr His Glu Leu Tyr Gln Gln Ser Asp Thr Trp Ser Leu 915 920 925 Ser Lys Thr Ser Leu Val Asn Glu 930 935 59126PRTHomo sapiens 59Met Pro Glu Leu Ala Lys Ser Ala Pro Ala Pro Lys Lys Gly Ser Lys 1 5 10 15 Lys Ala Val Thr Lys Ala Gln Lys Lys Asp Gly Lys Lys Arg Lys Arg 20 25 30 Ser Arg Lys Glu Ser Tyr Ser Val Tyr Val Tyr Lys Val Leu Lys Gln 35 40 45 Val His Pro Asp Thr Gly Ile Ser Ser Lys Ala Met Gly Ile Met Asn 50 55 60 Ser Phe Val Asn Asp Ile Phe Glu Arg Ile Ala Ser Glu Ala Ser Arg 65 70 75 80 Leu Ala His Tyr Asn Lys Arg Ser Thr Ile Thr Ser Arg Glu Ile Gln 85 90 95 Thr Ala Val Arg Leu Leu Leu Pro Gly Glu Leu Ala Lys His Ala Val 100 105 110 Ser Glu Gly Thr Lys Ala Val Thr Lys Tyr Thr Ser Ser Lys 115 120 125 60165PRTHomo sapiens 60Met Val Asn Pro Thr Val Phe Phe Asp Ile Ala Val Asp Gly Glu Pro 1 5 10 15 Leu Gly Arg Val Ser Phe Glu Leu Phe Ala Asp Lys Val Pro Lys Thr 20 25 30 Ala Glu Asn Phe Arg Ala Leu Ser Thr Gly Glu Lys Gly Phe Gly Tyr 35 40 45 Lys Gly Ser Cys Phe His Arg Ile Ile Pro Gly Phe Met Cys Gln Gly 50 55 60 Gly Asp Phe Thr Arg His Asn Gly Thr Gly Gly Lys Ser Ile Tyr Gly 65 70 75 80 Glu Lys Phe Glu Asp Glu Asn Phe Ile Leu Lys His Thr Gly Pro Gly 85 90 95 Ile Leu Ser Met Ala Asn Ala Gly Pro Asn Thr Asn Gly Ser Gln Phe 100 105 110 Phe Ile Cys Thr Ala Lys Thr Glu Trp Leu Asp Gly Lys His Val Val 115 120 125 Phe Gly Lys Val Lys Glu Gly Met Asn Ile Val Glu Ala Met Glu Arg 130 135 140 Phe Gly Ser Arg Asn Gly Lys Thr Ser Lys Lys Ile Thr Ile Ala Asp 145 150 155 160 Cys Gly Gln Leu Glu 165 61475PRTHomo sapiens 61Met Ala Asp Met Gln Asn Leu Val Glu Arg Leu Glu Arg Ala Val Gly 1 5 10 15 Arg Leu Glu Ala Val Ser His Thr Ser Asp Met His Arg Gly Tyr Ala 20 25 30 Asp Ser Pro Ser Lys Ala Gly Ala Ala Pro Tyr Val Gln Ala Phe Asp 35 40 45 Ser Leu Leu Ala Gly Pro Val Ala Glu Tyr Leu Lys Ile Ser Lys Glu 50 55 60 Ile Gly Gly Asp Val Gln Lys His Ala Glu Met Val His Thr Gly Leu 65 70 75 80 Lys Leu Glu Arg Ala Leu Leu Val Thr Ala Ser Gln Cys Gln Gln Pro 85 90 95 Ala Glu Asn Lys Leu Ser Asp Leu Leu Ala Pro Ile Ser Glu Gln Ile 100 105 110 Lys Glu Val Ile Thr Phe Arg Glu Lys Asn Arg Gly Ser Lys Leu Phe 115 120 125 Asn His Leu Ser Ala Val Ser Glu Ser Ile Gln Ala Leu Gly Trp Val 130 135 140 Ala Met Ala Pro Lys Pro Gly Pro Tyr Val Lys Glu Met Asn Asp Ala 145 150 155 160 Ala Met Phe Tyr Thr Asn Arg Val Leu Lys Glu Tyr Lys Asp Val Asp 165 170 175 Lys Lys His Val Asp Trp Val Lys Ala Tyr Leu Ser Ile Trp Thr Glu 180 185 190 Leu Gln Ala Tyr Ile Lys Glu Phe His Thr Thr Gly Leu Ala Trp Ser 195 200 205 Lys Thr Gly Pro Val Ala Lys Glu Leu Ser Gly Leu Pro Ser Gly Pro 210 215 220 Ser Ala Gly Ser Cys Pro Pro Pro Pro Pro Pro Cys Pro Pro Pro Pro 225 230 235 240 Pro Val Ser Thr Ile Ser Cys Ser Tyr Glu Ser Ala Ser Arg Ser Ser 245 250 255 Leu Phe Ala Gln Ile Asn Gln Gly Glu Ser Ile Thr His Ala Leu Lys 260 265 270 His Val Ser Asp Asp Met Lys Thr His Lys Asn Pro Ala Leu Lys Ala 275 280 285 Gln Ser Gly Pro Val Arg Ser Gly Pro Lys Pro Phe Ser Ala Pro Lys 290 295 300 Pro Gln Thr Ser Pro Ser Pro Lys Arg Ala Thr Lys Lys Glu Pro Ala 305 310 315 320 Val Leu Glu Leu Glu Gly Lys Lys Trp Arg Val Glu Asn Gln Glu Asn 325

330 335 Val Ser Asn Leu Val Ile Glu Asp Thr Glu Leu Lys Gln Val Ala Tyr 340 345 350 Ile Tyr Lys Cys Val Asn Thr Thr Leu Gln Ile Lys Gly Lys Ile Asn 355 360 365 Ser Ile Thr Val Asp Asn Cys Lys Lys Leu Gly Leu Val Phe Asp Asp 370 375 380 Val Val Gly Ile Val Glu Ile Ile Asn Ser Lys Asp Val Lys Val Gln 385 390 395 400 Val Met Gly Lys Val Pro Thr Ile Ser Ile Asn Lys Thr Asp Gly Cys 405 410 415 His Ala Tyr Leu Ser Lys Asn Ser Leu Asp Cys Glu Ile Val Ser Ala 420 425 430 Lys Ser Ser Glu Met Asn Val Leu Ile Pro Thr Glu Gly Gly Asp Phe 435 440 445 Asn Glu Phe Pro Val Pro Glu Gln Phe Lys Thr Leu Trp Asn Gly Gln 450 455 460 Lys Leu Val Thr Thr Val Thr Glu Ile Ala Gly 465 470 475 62452PRTHomo sapiens 62Met Ala Ala Ala Thr Leu Leu Arg Ala Thr Pro His Phe Ser Gly Leu 1 5 10 15 Ala Ala Gly Arg Thr Phe Leu Leu Gln Gly Leu Leu Arg Leu Leu Lys 20 25 30 Ala Pro Ala Leu Pro Leu Leu Cys Arg Gly Leu Ala Val Glu Ala Lys 35 40 45 Lys Thr Tyr Val Arg Asp Lys Pro His Val Asn Val Gly Thr Ile Gly 50 55 60 His Val Asp His Gly Lys Thr Thr Leu Thr Ala Ala Ile Thr Lys Ile 65 70 75 80 Leu Ala Glu Gly Gly Gly Ala Lys Phe Lys Lys Tyr Glu Glu Ile Asp 85 90 95 Asn Ala Pro Glu Glu Arg Ala Arg Gly Ile Thr Ile Asn Ala Ala His 100 105 110 Val Glu Tyr Ser Thr Ala Ala Arg His Tyr Ala His Thr Asp Cys Pro 115 120 125 Gly His Ala Asp Tyr Val Lys Asn Met Ile Thr Gly Thr Ala Pro Leu 130 135 140 Asp Gly Cys Ile Leu Val Val Ala Ala Asn Asp Gly Pro Met Pro Gln 145 150 155 160 Thr Arg Glu His Leu Leu Leu Ala Arg Gln Ile Gly Val Glu His Val 165 170 175 Val Val Tyr Val Asn Lys Ala Asp Ala Val Gln Asp Ser Glu Met Val 180 185 190 Glu Leu Val Glu Leu Glu Ile Arg Glu Leu Leu Thr Glu Phe Gly Tyr 195 200 205 Lys Gly Glu Glu Thr Pro Val Ile Val Gly Ser Ala Leu Cys Ala Leu 210 215 220 Glu Gly Arg Asp Pro Glu Leu Gly Leu Lys Ser Val Gln Lys Leu Leu 225 230 235 240 Asp Ala Val Asp Thr Tyr Ile Pro Val Pro Ala Arg Asp Leu Glu Lys 245 250 255 Pro Phe Leu Leu Pro Val Glu Ala Val Tyr Ser Val Pro Gly Arg Gly 260 265 270 Thr Val Val Thr Gly Thr Leu Glu Arg Gly Ile Leu Lys Lys Gly Asp 275 280 285 Glu Cys Glu Leu Leu Gly His Ser Lys Asn Ile Arg Thr Val Val Thr 290 295 300 Gly Ile Glu Met Phe His Lys Ser Leu Glu Arg Ala Glu Ala Gly Asp 305 310 315 320 Asn Leu Gly Ala Leu Val Arg Gly Leu Lys Arg Glu Asp Leu Arg Arg 325 330 335 Gly Leu Val Met Val Lys Pro Gly Ser Ile Lys Pro His Gln Lys Val 340 345 350 Glu Ala Gln Val Tyr Ile Leu Ser Lys Glu Glu Gly Gly Arg His Lys 355 360 365 Pro Phe Val Ser His Phe Met Pro Val Met Phe Ser Leu Thr Trp Asp 370 375 380 Met Ala Cys Arg Ile Ile Leu Pro Pro Glu Lys Glu Leu Ala Met Pro 385 390 395 400 Gly Glu Asp Leu Lys Phe Asn Leu Ile Leu Arg Gln Pro Met Ile Leu 405 410 415 Glu Lys Gly Gln Arg Phe Thr Leu Arg Asp Gly Asn Arg Thr Ile Gly 420 425 430 Thr Gly Leu Val Thr Asn Thr Leu Ala Met Thr Glu Glu Glu Lys Asn 435 440 445 Ile Lys Trp Gly 450 63226PRTHomo sapiens 63Met His Gln Thr Cys Val Arg Leu Glu Arg Glu Ala Ser Ala Arg Pro 1 5 10 15 Ser Pro Gly Pro Val Leu Pro Pro Arg Pro Leu Pro Ile Tyr Thr Glu 20 25 30 Leu Gln Ile Arg Glu Gly Pro Lys Arg Thr Ile Arg Ala Ala Ala Glu 35 40 45 Gly Ala Pro Cys Val Gly Arg Val Arg Cys Ala Pro Gly Asn Arg Gly 50 55 60 Gly Arg Glu Gly Ala Ser Gly Val Arg Gly Gly Val Ala Gln Val Pro 65 70 75 80 Pro Arg Leu Pro Ala Pro Pro Ile Gly Pro Glu Arg Asp Asp Leu Ala 85 90 95 Gly Gly Ala Gly Arg Lys Pro Leu Pro Ser Thr Ala Ala Ala Ser Ser 100 105 110 Pro Gly Ser Ala Ala Ala Ala Thr Ala Ala Leu Cys Pro Pro Ala Arg 115 120 125 Leu Ser Thr Pro Ser Met Ser Gly Leu Arg Val Tyr Ser Thr Ser Val 130 135 140 Thr Gly Ser Arg Glu Ile Lys Ser Gln Gln Ser Glu Val Thr Arg Ile 145 150 155 160 Leu Asp Gly Lys Arg Ile Gln Tyr Gln Leu Val Asp Ile Ser Gln Asp 165 170 175 Asn Ala Leu Arg Asp Glu Met Arg Ala Leu Ala Gly Asn Pro Lys Ala 180 185 190 Thr Pro Pro Gln Ile Val Asn Gly Asp Gln Tyr Cys Gly Asp Tyr Glu 195 200 205 Leu Phe Val Glu Ala Val Glu Gln Asn Thr Leu Gln Glu Phe Leu Lys 210 215 220 Leu Ala 225 6489PRTHomo sapiens 64Met Ser Ser Gln Gln Gln Lys Gln Pro Cys Thr Pro Pro Pro Gln Leu 1 5 10 15 Gln Gln Gln Gln Val Lys Gln Pro Cys Gln Pro Pro Pro Gln Glu Pro 20 25 30 Cys Ile Pro Lys Thr Lys Glu Pro Cys His Pro Lys Val Pro Glu Pro 35 40 45 Cys His Pro Lys Val Pro Glu Pro Cys Gln Pro Lys Val Pro Glu Pro 50 55 60 Cys His Pro Lys Val Pro Glu Pro Cys Pro Ser Ile Val Thr Pro Ala 65 70 75 80 Pro Ala Gln Gln Lys Thr Lys Gln Lys 85 651822PRTHomo sapiens 65Met Ala Gly Pro Arg Pro Ser Pro Trp Ala Arg Leu Leu Leu Ala Ala 1 5 10 15 Leu Ile Ser Val Ser Leu Ser Gly Thr Leu Ala Asn Arg Cys Lys Lys 20 25 30 Ala Pro Val Lys Ser Cys Thr Glu Cys Val Arg Val Asp Lys Asp Cys 35 40 45 Ala Tyr Cys Thr Asp Glu Met Phe Arg Asp Arg Arg Cys Asn Thr Gln 50 55 60 Ala Glu Leu Leu Ala Ala Gly Cys Gln Arg Glu Ser Ile Val Val Met 65 70 75 80 Glu Ser Ser Phe Gln Ile Thr Glu Glu Thr Gln Ile Asp Thr Thr Leu 85 90 95 Arg Arg Ser Gln Met Ser Pro Gln Gly Leu Arg Val Arg Leu Arg Pro 100 105 110 Gly Glu Glu Arg His Phe Glu Leu Glu Val Phe Glu Pro Leu Glu Ser 115 120 125 Pro Val Asp Leu Tyr Ile Leu Met Asp Phe Ser Asn Ser Met Ser Asp 130 135 140 Asp Leu Asp Asn Leu Lys Lys Met Gly Gln Asn Leu Ala Arg Val Leu 145 150 155 160 Ser Gln Leu Thr Ser Asp Tyr Thr Ile Gly Phe Gly Lys Phe Val Asp 165 170 175 Lys Val Ser Val Pro Gln Thr Asp Met Arg Pro Glu Lys Leu Lys Glu 180 185 190 Pro Trp Pro Asn Ser Asp Pro Pro Phe Ser Phe Lys Asn Val Ile Ser 195 200 205 Leu Thr Glu Asp Val Asp Glu Phe Arg Asn Lys Leu Gln Gly Glu Arg 210 215 220 Ile Ser Gly Asn Leu Asp Ala Pro Glu Gly Gly Phe Asp Ala Ile Leu 225 230 235 240 Gln Thr Ala Val Cys Thr Arg Asp Ile Gly Trp Arg Pro Asp Ser Thr 245 250 255 His Leu Leu Val Phe Ser Thr Glu Ser Ala Phe His Tyr Glu Ala Asp 260 265 270 Gly Ala Asn Val Leu Ala Gly Ile Met Ser Arg Asn Asp Glu Arg Cys 275 280 285 His Leu Asp Thr Thr Gly Thr Tyr Thr Gln Tyr Arg Thr Gln Asp Tyr 290 295 300 Pro Ser Val Pro Thr Leu Val Arg Leu Leu Ala Lys His Asn Ile Ile 305 310 315 320 Pro Ile Phe Ala Val Thr Asn Tyr Ser Tyr Ser Tyr Tyr Glu Lys Leu 325 330 335 His Thr Tyr Phe Pro Val Ser Ser Leu Gly Val Leu Gln Glu Asp Ser 340 345 350 Ser Asn Ile Val Glu Leu Leu Glu Glu Ala Phe Asn Arg Ile Arg Ser 355 360 365 Asn Leu Asp Ile Arg Ala Leu Asp Ser Pro Arg Gly Leu Arg Thr Glu 370 375 380 Val Thr Ser Lys Met Phe Gln Lys Thr Arg Thr Gly Ser Phe His Ile 385 390 395 400 Arg Arg Gly Glu Val Gly Ile Tyr Gln Val Gln Leu Arg Ala Leu Glu 405 410 415 His Val Asp Gly Thr His Val Cys Gln Leu Pro Glu Asp Gln Lys Gly 420 425 430 Asn Ile His Leu Lys Pro Ser Phe Ser Asp Gly Leu Lys Met Asp Ala 435 440 445 Gly Ile Ile Cys Asp Val Cys Thr Cys Glu Leu Gln Lys Glu Val Arg 450 455 460 Ser Ala Arg Cys Ser Phe Asn Gly Asp Phe Val Cys Gly Gln Cys Val 465 470 475 480 Cys Ser Glu Gly Trp Ser Gly Gln Thr Cys Asn Cys Ser Thr Gly Ser 485 490 495 Leu Ser Asp Ile Gln Pro Cys Leu Arg Glu Gly Glu Asp Lys Pro Cys 500 505 510 Ser Gly Arg Gly Glu Cys Gln Cys Gly His Cys Val Cys Tyr Gly Glu 515 520 525 Gly Arg Tyr Glu Gly Gln Phe Cys Glu Tyr Asp Asn Phe Gln Cys Pro 530 535 540 Arg Thr Ser Gly Phe Leu Cys Asn Asp Arg Gly Arg Cys Ser Met Gly 545 550 555 560 Gln Cys Val Cys Glu Pro Gly Trp Thr Gly Pro Ser Cys Asp Cys Pro 565 570 575 Leu Ser Asn Ala Thr Cys Ile Asp Ser Asn Gly Gly Ile Cys Asn Gly 580 585 590 Arg Gly His Cys Glu Cys Gly Arg Cys His Cys His Gln Gln Ser Leu 595 600 605 Tyr Thr Asp Thr Ile Cys Glu Ile Asn Tyr Ser Ala Ile His Pro Gly 610 615 620 Leu Cys Glu Asp Leu Arg Ser Cys Val Gln Cys Gln Ala Trp Gly Thr 625 630 635 640 Gly Glu Lys Lys Gly Arg Thr Cys Glu Glu Cys Asn Phe Lys Val Lys 645 650 655 Met Val Asp Glu Leu Lys Arg Ala Glu Glu Val Val Val Arg Cys Ser 660 665 670 Phe Arg Asp Glu Asp Asp Asp Cys Thr Tyr Ser Tyr Thr Met Glu Gly 675 680 685 Asp Gly Ala Pro Gly Pro Asn Ser Thr Val Leu Val His Lys Lys Lys 690 695 700 Asp Cys Pro Pro Gly Ser Phe Trp Trp Leu Ile Pro Leu Leu Leu Leu 705 710 715 720 Leu Leu Pro Leu Leu Ala Leu Leu Leu Leu Leu Cys Trp Lys Tyr Cys 725 730 735 Ala Cys Cys Lys Ala Cys Leu Ala Leu Leu Pro Cys Cys Asn Arg Gly 740 745 750 His Met Val Gly Phe Lys Glu Asp His Tyr Met Leu Arg Glu Asn Leu 755 760 765 Met Ala Ser Asp His Leu Asp Thr Pro Met Leu Arg Ser Gly Asn Leu 770 775 780 Lys Gly Arg Asp Val Val Arg Trp Lys Val Thr Asn Asn Met Gln Arg 785 790 795 800 Pro Gly Phe Ala Thr His Ala Ala Ser Ile Asn Pro Thr Glu Leu Val 805 810 815 Pro Tyr Gly Leu Ser Leu Arg Leu Ala Arg Leu Cys Thr Glu Asn Leu 820 825 830 Leu Lys Pro Asp Thr Arg Glu Cys Ala Gln Leu Arg Gln Glu Val Glu 835 840 845 Glu Asn Leu Asn Glu Val Tyr Arg Gln Ile Ser Gly Val His Lys Leu 850 855 860 Gln Gln Thr Lys Phe Arg Gln Gln Pro Asn Ala Gly Lys Lys Gln Asp 865 870 875 880 His Thr Ile Val Asp Thr Val Leu Met Ala Pro Arg Ser Ala Lys Pro 885 890 895 Ala Leu Leu Lys Leu Thr Glu Lys Gln Val Glu Gln Arg Ala Phe His 900 905 910 Asp Leu Lys Val Ala Pro Gly Tyr Tyr Thr Leu Thr Ala Asp Gln Asp 915 920 925 Ala Arg Gly Met Val Glu Phe Gln Glu Gly Val Glu Leu Val Asp Val 930 935 940 Arg Val Pro Leu Phe Ile Arg Pro Glu Asp Asp Asp Glu Lys Gln Leu 945 950 955 960 Leu Val Glu Ala Ile Asp Val Pro Ala Gly Thr Ala Thr Leu Gly Arg 965 970 975 Arg Leu Val Asn Ile Thr Ile Ile Lys Glu Gln Ala Arg Asp Val Val 980 985 990 Ser Phe Glu Gln Pro Glu Phe Ser Val Ser Arg Gly Asp Gln Val Ala 995 1000 1005 Arg Ile Pro Val Ile Arg Arg Val Leu Asp Gly Gly Lys Ser Gln 1010 1015 1020 Val Ser Tyr Arg Thr Gln Asp Gly Thr Ala Gln Gly Asn Arg Asp 1025 1030 1035 Tyr Ile Pro Val Glu Gly Glu Leu Leu Phe Gln Pro Gly Glu Ala 1040 1045 1050 Trp Lys Glu Leu Gln Val Lys Leu Leu Glu Leu Gln Glu Val Asp 1055 1060 1065 Ser Leu Leu Arg Gly Arg Gln Val Arg Arg Phe His Val Gln Leu 1070 1075 1080 Ser Asn Pro Lys Phe Gly Ala His Leu Gly Gln Pro His Ser Thr 1085 1090 1095 Thr Ile Ile Ile Arg Asp Pro Asp Glu Leu Asp Arg Ser Phe Thr 1100 1105 1110 Ser Gln Met Leu Ser Ser Gln Pro Pro Pro His Gly Asp Leu Gly 1115 1120 1125 Ala Pro Gln Asn Pro Asn Ala Lys Ala Ala Gly Ser Arg Lys Ile 1130 1135 1140 His Phe Asn Trp Leu Pro Pro Ser Gly Lys Pro Met Gly Tyr Arg 1145 1150 1155 Val Lys Tyr Trp Ile Gln Gly Asp Ser Glu Ser Glu Ala His Leu 1160 1165 1170 Leu Asp Ser Lys Val Pro Ser Val Glu Leu Thr Asn Leu Tyr Pro 1175 1180 1185 Tyr Cys Asp Tyr Glu Met Lys Val Cys Ala Tyr Gly Ala Gln Gly 1190 1195 1200 Glu Gly Pro Tyr Ser Ser Leu Val Ser Cys Arg Thr His Gln Glu 1205 1210 1215 Val Pro Ser Glu Pro Gly Arg Leu Ala Phe Asn Val Val Ser Ser 1220 1225 1230 Thr Val Thr Gln Leu Ser Trp Ala Glu Pro Ala Glu Thr Asn Gly 1235 1240 1245 Glu Ile Thr Ala Tyr Glu Val Cys Tyr Gly Leu Val Asn Asp Asp 1250 1255 1260 Asn Arg Pro Ile Gly Pro Met Lys Lys Val Leu Val Asp Asn Pro 1265 1270 1275 Lys Asn Arg Met Leu Leu Ile Glu Asn Leu Arg Glu Ser Gln Pro 1280 1285 1290 Tyr Arg Tyr Thr Val Lys Ala Arg Asn Gly Ala Gly Trp Gly Pro 1295 1300 1305 Glu Arg Glu Ala Ile Ile Asn Leu Ala Thr Gln Pro Lys Arg Pro 1310 1315 1320 Met Ser Ile Pro Ile Ile Pro Asp Ile Pro Ile Val Asp Ala Gln 1325 1330 1335 Ser Gly Glu Asp Tyr Asp Ser Phe Leu Met Tyr Ser Asp Asp Val 1340 1345 1350 Leu Arg Ser Pro Ser Gly Ser Gln Arg Pro Ser Val Ser Asp Asp 1355 1360 1365

Thr Gly Cys Gly Trp Lys Phe Glu Pro Leu Leu Gly Glu Glu Leu 1370 1375 1380 Asp Leu Arg Arg Val Thr Trp Arg Leu Pro Pro Glu Leu Ile Pro 1385 1390 1395 Arg Leu Ser Ala Ser Ser Gly Arg Ser Ser Asp Ala Glu Ala Pro 1400 1405 1410 His Gly Pro Pro Asp Asp Gly Gly Ala Gly Gly Lys Gly Gly Ser 1415 1420 1425 Leu Pro Arg Ser Ala Thr Pro Gly Pro Pro Gly Glu His Leu Val 1430 1435 1440 Asn Gly Arg Met Asp Phe Ala Phe Pro Gly Ser Thr Asn Ser Leu 1445 1450 1455 His Arg Met Thr Thr Thr Ser Ala Ala Ala Tyr Gly Thr His Leu 1460 1465 1470 Ser Pro His Val Pro His Arg Val Leu Ser Thr Ser Ser Thr Leu 1475 1480 1485 Thr Arg Asp Tyr Asn Ser Leu Thr Arg Ser Glu His Ser His Ser 1490 1495 1500 Thr Thr Leu Pro Arg Asp Tyr Ser Thr Leu Thr Ser Val Ser Ser 1505 1510 1515 His Asp Ser Arg Leu Thr Ala Gly Val Pro Asp Thr Pro Thr Arg 1520 1525 1530 Leu Val Phe Ser Ala Leu Gly Pro Thr Ser Leu Arg Val Ser Trp 1535 1540 1545 Gln Glu Pro Arg Cys Glu Arg Pro Leu Gln Gly Tyr Ser Val Glu 1550 1555 1560 Tyr Gln Leu Leu Asn Gly Gly Glu Leu His Arg Leu Asn Ile Pro 1565 1570 1575 Asn Pro Ala Gln Thr Ser Val Val Val Glu Asp Leu Leu Pro Asn 1580 1585 1590 His Ser Tyr Val Phe Arg Val Arg Ala Gln Ser Gln Glu Gly Trp 1595 1600 1605 Gly Arg Glu Arg Glu Gly Val Ile Thr Ile Glu Ser Gln Val His 1610 1615 1620 Pro Gln Ser Pro Leu Cys Pro Leu Pro Gly Ser Ala Phe Thr Leu 1625 1630 1635 Ser Thr Pro Ser Ala Pro Gly Pro Leu Val Phe Thr Ala Leu Ser 1640 1645 1650 Pro Asp Ser Leu Gln Leu Ser Trp Glu Arg Pro Arg Arg Pro Asn 1655 1660 1665 Gly Asp Ile Val Gly Tyr Leu Val Thr Cys Glu Met Ala Gln Gly 1670 1675 1680 Gly Gly Pro Ala Thr Ala Phe Arg Val Asp Gly Asp Ser Pro Glu 1685 1690 1695 Ser Arg Leu Thr Val Pro Gly Leu Ser Glu Asn Val Pro Tyr Lys 1700 1705 1710 Phe Lys Val Gln Ala Arg Thr Thr Glu Gly Phe Gly Pro Glu Arg 1715 1720 1725 Glu Gly Ile Ile Thr Ile Glu Ser Gln Asp Gly Gly Pro Phe Pro 1730 1735 1740 Gln Leu Gly Ser Arg Ala Gly Leu Phe Gln His Pro Leu Gln Ser 1745 1750 1755 Glu Tyr Ser Ser Ile Thr Thr Thr His Thr Ser Ala Thr Glu Pro 1760 1765 1770 Phe Leu Val Asp Gly Leu Thr Leu Gly Ala Gln His Leu Glu Ala 1775 1780 1785 Gly Gly Ser Leu Thr Arg His Val Thr Gln Glu Phe Val Ser Arg 1790 1795 1800 Thr Leu Thr Thr Ser Gly Thr Leu Ser Thr His Met Asp Gln Gln 1805 1810 1815 Phe Phe Gln Thr 1820 66123PRTHomo sapiens 66Met Ala Lys Ile Lys Ala Arg Asp Leu Arg Gly Lys Lys Lys Glu Glu 1 5 10 15 Leu Leu Lys Gln Leu Asp Asp Leu Lys Val Glu Leu Ser Gln Leu Arg 20 25 30 Val Ala Lys Val Thr Gly Gly Ala Ala Ser Lys Leu Ser Lys Ile Arg 35 40 45 Val Val Arg Lys Ser Ile Ala Arg Val Leu Thr Val Ile Asn Gln Thr 50 55 60 Gln Lys Glu Asn Leu Arg Lys Phe Tyr Lys Gly Lys Lys Tyr Lys Pro 65 70 75 80 Leu Asp Leu Arg Pro Lys Lys Thr Arg Ala Met Arg Arg Arg Leu Asn 85 90 95 Lys His Glu Glu Asn Leu Lys Thr Lys Lys Gln Gln Arg Lys Glu Arg 100 105 110 Leu Tyr Pro Leu Arg Lys Tyr Ala Val Lys Ala 115 120 67117PRTHomo sapiens 67Met Val Gln Arg Leu Thr Tyr Arg Arg Arg Leu Ser Tyr Asn Thr Ala 1 5 10 15 Ser Asn Lys Thr Arg Leu Ser Arg Thr Pro Gly Asn Arg Ile Val Tyr 20 25 30 Leu Tyr Thr Lys Lys Val Gly Lys Ala Pro Lys Ser Ala Cys Gly Val 35 40 45 Cys Pro Gly Arg Leu Arg Gly Val Arg Ala Val Arg Pro Lys Val Leu 50 55 60 Met Arg Leu Ser Lys Thr Lys Lys His Val Ser Arg Ala Tyr Gly Gly 65 70 75 80 Ser Met Cys Ala Lys Cys Val Arg Asp Arg Ile Lys Arg Ala Phe Leu 85 90 95 Ile Glu Glu Gln Lys Ile Val Val Lys Val Leu Lys Ala Gln Ala Gln 100 105 110 Ser Gln Lys Ala Lys 115 6893PRTHomo sapiens 68Met Leu Thr Glu Leu Glu Lys Ala Leu Asn Ser Ile Ile Asp Val Tyr 1 5 10 15 His Lys Tyr Ser Leu Ile Lys Gly Asn Phe His Ala Val Tyr Arg Asp 20 25 30 Asp Leu Lys Lys Leu Leu Glu Thr Glu Cys Pro Gln Tyr Ile Arg Lys 35 40 45 Lys Gly Ala Asp Val Trp Phe Lys Glu Leu Asp Ile Asn Thr Asp Gly 50 55 60 Ala Val Asn Phe Gln Glu Phe Leu Ile Leu Val Ile Lys Met Gly Val 65 70 75 80 Ala Ala His Lys Lys Ser His Glu Glu Ser His Lys Glu 85 90 69803PRTHomo sapiens 69Met Arg Ala Leu Trp Val Leu Gly Leu Cys Cys Val Leu Leu Thr Phe 1 5 10 15 Gly Ser Val Arg Ala Asp Asp Glu Val Asp Val Asp Gly Thr Val Glu 20 25 30 Glu Asp Leu Gly Lys Ser Arg Glu Gly Ser Arg Thr Asp Asp Glu Val 35 40 45 Val Gln Arg Glu Glu Glu Ala Ile Gln Leu Asp Gly Leu Asn Ala Ser 50 55 60 Gln Ile Arg Glu Leu Arg Glu Lys Ser Glu Lys Phe Ala Phe Gln Ala 65 70 75 80 Glu Val Asn Arg Met Met Lys Leu Ile Ile Asn Ser Leu Tyr Lys Asn 85 90 95 Lys Glu Ile Phe Leu Arg Glu Leu Ile Ser Asn Ala Ser Asp Ala Leu 100 105 110 Asp Lys Ile Arg Leu Ile Ser Leu Thr Asp Glu Asn Ala Leu Ser Gly 115 120 125 Asn Glu Glu Leu Thr Val Lys Ile Lys Cys Asp Lys Glu Lys Asn Leu 130 135 140 Leu His Val Thr Asp Thr Gly Val Gly Met Thr Arg Glu Glu Leu Val 145 150 155 160 Lys Asn Leu Gly Thr Ile Ala Lys Ser Gly Thr Ser Glu Phe Leu Asn 165 170 175 Lys Met Thr Glu Ala Gln Glu Asp Gly Gln Ser Thr Ser Glu Leu Ile 180 185 190 Gly Gln Phe Gly Val Gly Phe Tyr Ser Ala Phe Leu Val Ala Asp Lys 195 200 205 Val Ile Val Thr Ser Lys His Asn Asn Asp Thr Gln His Ile Trp Glu 210 215 220 Ser Asp Ser Asn Glu Phe Ser Val Ile Ala Asp Pro Arg Gly Asn Thr 225 230 235 240 Leu Gly Arg Gly Thr Thr Ile Thr Leu Val Leu Lys Glu Glu Ala Ser 245 250 255 Asp Tyr Leu Glu Leu Asp Thr Ile Lys Asn Leu Val Lys Lys Tyr Ser 260 265 270 Gln Phe Ile Asn Phe Pro Ile Tyr Val Trp Ser Ser Lys Thr Glu Thr 275 280 285 Val Glu Glu Pro Met Glu Glu Glu Glu Ala Ala Lys Glu Glu Lys Glu 290 295 300 Glu Ser Asp Asp Glu Ala Ala Val Glu Glu Glu Glu Glu Glu Lys Lys 305 310 315 320 Pro Lys Thr Lys Lys Val Glu Lys Thr Val Trp Asp Trp Glu Leu Met 325 330 335 Asn Asp Ile Lys Pro Ile Trp Gln Arg Pro Ser Lys Glu Val Glu Glu 340 345 350 Asp Glu Tyr Lys Ala Phe Tyr Lys Ser Phe Ser Lys Glu Ser Asp Asp 355 360 365 Pro Met Ala Tyr Ile His Phe Thr Ala Glu Gly Glu Val Thr Phe Lys 370 375 380 Ser Ile Leu Phe Val Pro Thr Ser Ala Pro Arg Gly Leu Phe Asp Glu 385 390 395 400 Tyr Gly Ser Lys Lys Ser Asp Tyr Ile Lys Leu Tyr Val Arg Arg Val 405 410 415 Phe Ile Thr Asp Asp Phe His Asp Met Met Pro Lys Tyr Leu Asn Phe 420 425 430 Val Lys Gly Val Val Asp Ser Asp Asp Leu Pro Leu Asn Val Ser Arg 435 440 445 Glu Thr Leu Gln Gln His Lys Leu Leu Lys Val Ile Arg Lys Lys Leu 450 455 460 Val Arg Lys Thr Leu Asp Met Ile Lys Lys Ile Ala Asp Asp Lys Tyr 465 470 475 480 Asn Asp Thr Phe Trp Lys Glu Phe Gly Thr Asn Ile Lys Leu Gly Val 485 490 495 Ile Glu Asp His Ser Asn Arg Thr Arg Leu Ala Lys Leu Leu Arg Phe 500 505 510 Gln Ser Ser His His Pro Thr Asp Ile Thr Ser Leu Asp Gln Tyr Val 515 520 525 Glu Arg Met Lys Glu Lys Gln Asp Lys Ile Tyr Phe Met Ala Gly Ser 530 535 540 Ser Arg Lys Glu Ala Glu Ser Ser Pro Phe Val Glu Arg Leu Leu Lys 545 550 555 560 Lys Gly Tyr Glu Val Ile Tyr Leu Thr Glu Pro Val Asp Glu Tyr Cys 565 570 575 Ile Gln Ala Leu Pro Glu Phe Asp Gly Lys Arg Phe Gln Asn Val Ala 580 585 590 Lys Glu Gly Val Lys Phe Asp Glu Ser Glu Lys Thr Lys Glu Ser Arg 595 600 605 Glu Ala Val Glu Lys Glu Phe Glu Pro Leu Leu Asn Trp Met Lys Asp 610 615 620 Lys Ala Leu Lys Asp Lys Ile Glu Lys Ala Val Val Ser Gln Arg Leu 625 630 635 640 Thr Glu Ser Pro Cys Ala Leu Val Ala Ser Gln Tyr Gly Trp Ser Gly 645 650 655 Asn Met Glu Arg Ile Met Lys Ala Gln Ala Tyr Gln Thr Gly Lys Asp 660 665 670 Ile Ser Thr Asn Tyr Tyr Ala Ser Gln Lys Lys Thr Phe Glu Ile Asn 675 680 685 Pro Arg His Pro Leu Ile Arg Asp Met Leu Arg Arg Ile Lys Glu Asp 690 695 700 Glu Asp Asp Lys Thr Val Leu Asp Leu Ala Val Val Leu Phe Glu Thr 705 710 715 720 Ala Thr Leu Arg Ser Gly Tyr Leu Leu Pro Asp Thr Lys Ala Tyr Gly 725 730 735 Asp Arg Ile Glu Arg Met Leu Arg Leu Ser Leu Asn Ile Asp Pro Asp 740 745 750 Ala Lys Val Glu Glu Glu Pro Glu Glu Glu Pro Glu Glu Thr Ala Glu 755 760 765 Asp Thr Thr Glu Asp Thr Glu Gln Asp Glu Asp Glu Glu Met Asp Val 770 775 780 Gly Thr Asp Glu Glu Glu Glu Thr Ala Lys Glu Ser Thr Ala Glu Lys 785 790 795 800 Asp Glu Leu 70142PRTHomo sapiens 70Met Val Leu Ser Pro Ala Asp Lys Thr Asn Val Lys Ala Ala Trp Gly 1 5 10 15 Lys Val Gly Ala His Ala Gly Glu Tyr Gly Ala Glu Ala Leu Glu Arg 20 25 30 Met Phe Leu Ser Phe Pro Thr Thr Lys Thr Tyr Phe Pro His Phe Asp 35 40 45 Leu Ser His Gly Ser Ala Gln Val Lys Gly His Gly Lys Lys Val Ala 50 55 60 Asp Ala Leu Thr Asn Ala Val Ala His Val Asp Asp Met Pro Asn Ala 65 70 75 80 Leu Ser Ala Leu Ser Asp Leu His Ala His Lys Leu Arg Val Asp Pro 85 90 95 Val Asn Phe Lys Leu Leu Ser His Cys Leu Leu Val Thr Leu Ala Ala 100 105 110 His Leu Pro Ala Glu Phe Thr Pro Ala Val His Ala Ser Leu Asp Lys 115 120 125 Phe Leu Ala Ser Val Ser Thr Val Leu Thr Ser Lys Tyr Arg 130 135 140 71248PRTHomo sapiens 71Met Glu Arg Ala Ser Leu Ile Gln Lys Ala Lys Leu Ala Glu Gln Ala 1 5 10 15 Glu Arg Tyr Glu Asp Met Ala Ala Phe Met Lys Gly Ala Val Glu Lys 20 25 30 Gly Glu Glu Leu Ser Cys Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr 35 40 45 Lys Asn Val Val Gly Gly Gln Arg Ala Ala Trp Arg Val Leu Ser Ser 50 55 60 Ile Glu Gln Lys Ser Asn Glu Glu Gly Ser Glu Glu Lys Gly Pro Glu 65 70 75 80 Val Arg Glu Tyr Arg Glu Lys Val Glu Thr Glu Leu Gln Gly Val Cys 85 90 95 Asp Thr Val Leu Gly Leu Leu Asp Ser His Leu Ile Lys Glu Ala Gly 100 105 110 Asp Ala Glu Ser Arg Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Tyr 115 120 125 Arg Tyr Leu Ala Glu Val Ala Thr Gly Asp Asp Lys Lys Arg Ile Ile 130 135 140 Asp Ser Ala Arg Ser Ala Tyr Gln Glu Ala Met Asp Ile Ser Lys Lys 145 150 155 160 Glu Met Pro Pro Thr Asn Pro Ile Arg Leu Gly Leu Ala Leu Asn Phe 165 170 175 Ser Val Phe His Tyr Glu Ile Ala Asn Ser Pro Glu Glu Ala Ile Ser 180 185 190 Leu Ala Lys Thr Thr Phe Asp Glu Ala Met Ala Asp Leu His Thr Leu 195 200 205 Ser Glu Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln Leu Leu Arg 210 215 220 Asp Asn Leu Thr Leu Trp Thr Ala Asp Asn Ala Gly Glu Glu Gly Gly 225 230 235 240 Glu Ala Pro Gln Glu Pro Gln Ser 245 72732PRTHomo sapiens 72Met Pro Glu Glu Thr Gln Thr Gln Asp Gln Pro Met Glu Glu Glu Glu 1 5 10 15 Val Glu Thr Phe Ala Phe Gln Ala Glu Ile Ala Gln Leu Met Ser Leu 20 25 30 Ile Ile Asn Thr Phe Tyr Ser Asn Lys Glu Ile Phe Leu Arg Glu Leu 35 40 45 Ile Ser Asn Ser Ser Asp Ala Leu Asp Lys Ile Arg Tyr Glu Ser Leu 50 55 60 Thr Asp Pro Ser Lys Leu Asp Ser Gly Lys Glu Leu His Ile Asn Leu 65 70 75 80 Ile Pro Asn Lys Gln Asp Arg Thr Leu Thr Ile Val Asp Thr Gly Ile 85 90 95 Gly Met Thr Lys Ala Asp Leu Ile Asn Asn Leu Gly Thr Ile Ala Lys 100 105 110 Ser Gly Thr Lys Ala Phe Met Glu Ala Leu Gln Ala Gly Ala Asp Ile 115 120 125 Ser Met Ile Gly Gln Phe Gly Val Gly Phe Tyr Ser Ala Tyr Leu Val 130 135 140 Ala Glu Lys Val Thr Val Ile Thr Lys His Asn Asp Asp Glu Gln Tyr 145 150 155 160 Ala Trp Glu Ser Ser Ala Gly Gly Ser Phe Thr Val Arg Thr Asp Thr 165 170 175 Gly Glu Pro Met Gly Arg Gly Thr Lys Val Ile Leu His Leu Lys Glu 180 185 190 Asp Gln Thr Glu Tyr Leu Glu Glu Arg Arg Ile Lys Glu Ile Val Lys 195 200 205 Lys His Ser Gln Phe Ile Gly Tyr Pro Ile Thr Leu Phe Val Glu Lys 210 215 220 Glu Arg Asp Lys Glu Val Ser Asp Asp Glu Ala Glu Glu Lys Glu Asp 225 230 235 240 Lys Glu Glu Glu Lys Glu Lys Glu Glu Lys Glu Ser Glu Asp Lys Pro 245 250 255 Glu Ile Glu Asp Val Gly Ser Asp Glu Glu Glu Glu Lys Lys Asp Gly 260 265 270 Asp Lys Lys Lys Lys Lys Lys Ile Lys Glu Lys Tyr Ile Asp Gln Glu 275 280

285 Glu Leu Asn Lys Thr Lys Pro Ile Trp Thr Arg Asn Pro Asp Asp Ile 290 295 300 Thr Asn Glu Glu Tyr Gly Glu Phe Tyr Lys Ser Leu Thr Asn Asp Trp 305 310 315 320 Glu Asp His Leu Ala Val Lys His Phe Ser Val Glu Gly Gln Leu Glu 325 330 335 Phe Arg Ala Leu Leu Phe Val Pro Arg Arg Ala Pro Phe Asp Leu Phe 340 345 350 Glu Asn Arg Lys Lys Lys Asn Asn Ile Lys Leu Tyr Val Arg Arg Val 355 360 365 Phe Ile Met Asp Asn Cys Glu Glu Leu Ile Pro Glu Tyr Leu Asn Phe 370 375 380 Ile Arg Gly Val Val Asp Ser Glu Asp Leu Pro Leu Asn Ile Ser Arg 385 390 395 400 Glu Met Leu Gln Gln Ser Lys Ile Leu Lys Val Ile Arg Lys Asn Leu 405 410 415 Val Lys Lys Cys Leu Glu Leu Phe Thr Glu Leu Ala Glu Asp Lys Glu 420 425 430 Asn Tyr Lys Lys Phe Tyr Glu Gln Phe Ser Lys Asn Ile Lys Leu Gly 435 440 445 Ile His Glu Asp Ser Gln Asn Arg Lys Lys Leu Ser Glu Leu Leu Arg 450 455 460 Tyr Tyr Thr Ser Ala Ser Gly Asp Glu Met Val Ser Leu Lys Asp Tyr 465 470 475 480 Cys Thr Arg Met Lys Glu Asn Gln Lys His Ile Tyr Tyr Ile Thr Gly 485 490 495 Glu Thr Lys Asp Gln Val Ala Asn Ser Ala Phe Val Glu Arg Leu Arg 500 505 510 Lys His Gly Leu Glu Val Ile Tyr Met Ile Glu Pro Ile Asp Glu Tyr 515 520 525 Cys Val Gln Gln Leu Lys Glu Phe Glu Gly Lys Thr Leu Val Ser Val 530 535 540 Thr Lys Glu Gly Leu Glu Leu Pro Glu Asp Glu Glu Glu Lys Lys Lys 545 550 555 560 Gln Glu Glu Lys Lys Thr Lys Phe Glu Asn Leu Cys Lys Ile Met Lys 565 570 575 Asp Ile Leu Glu Lys Lys Val Glu Lys Val Val Val Ser Asn Arg Leu 580 585 590 Val Thr Ser Pro Cys Cys Ile Val Thr Ser Thr Tyr Gly Trp Thr Ala 595 600 605 Asn Met Glu Arg Ile Met Lys Ala Gln Ala Leu Arg Asp Asn Ser Thr 610 615 620 Met Gly Tyr Met Ala Ala Lys Lys His Leu Glu Ile Asn Pro Asp His 625 630 635 640 Ser Ile Ile Glu Thr Leu Arg Gln Lys Ala Glu Ala Asp Lys Asn Asp 645 650 655 Lys Ser Val Lys Asp Leu Val Ile Leu Leu Tyr Glu Thr Ala Leu Leu 660 665 670 Ser Ser Gly Phe Ser Leu Glu Asp Pro Gln Thr His Ala Asn Arg Ile 675 680 685 Tyr Arg Met Ile Lys Leu Gly Leu Gly Ile Asp Glu Asp Asp Pro Thr 690 695 700 Ala Asp Asp Thr Ser Ala Ala Val Thr Glu Glu Met Pro Pro Leu Glu 705 710 715 720 Gly Asp Asp Asp Thr Ser Arg Met Glu Glu Val Asp 725 730 73114PRTHomo sapiens 73Met Thr Cys Lys Met Ser Gln Leu Glu Arg Asn Ile Glu Thr Ile Ile 1 5 10 15 Asn Thr Phe His Gln Tyr Ser Val Lys Leu Gly His Pro Asp Thr Leu 20 25 30 Asn Gln Gly Glu Phe Lys Glu Leu Val Arg Lys Asp Leu Gln Asn Phe 35 40 45 Leu Lys Lys Glu Asn Lys Asn Glu Lys Val Ile Glu His Ile Met Glu 50 55 60 Asp Leu Asp Thr Asn Ala Asp Lys Gln Leu Ser Phe Glu Glu Phe Ile 65 70 75 80 Met Leu Met Ala Arg Leu Thr Trp Ala Ser His Glu Lys Met His Glu 85 90 95 Gly Asp Glu Gly Pro Gly His His His Lys Pro Gly Leu Gly Glu Gly 100 105 110 Thr Pro 74586PRTHomo sapiens 74Met Ala Lys Ala Ala Ala Ile Gly Ile Asp Leu Gly Thr Thr Tyr Ser 1 5 10 15 Cys Val Gly Val Phe Gln His Gly Lys Val Glu Ile Ile Ala Asn Asp 20 25 30 Gln Gly Asn Arg Thr Thr Pro Ser Tyr Val Ala Phe Thr Asp Thr Glu 35 40 45 Arg Leu Ile Gly Asp Ala Ala Lys Asn Gln Val Ala Leu Asn Pro Gln 50 55 60 Asn Thr Val Phe Asp Ala Lys Arg Leu Ile Gly Arg Lys Phe Gly Asp 65 70 75 80 Pro Val Val Gln Ser Asp Met Lys His Trp Pro Phe Gln Val Ile Asn 85 90 95 Asp Ser Gln Arg Gln Ala Thr Lys Asp Ala Gly Val Ile Ala Gly Leu 100 105 110 Asn Val Leu Arg Ile Ile Asn Glu Pro Thr Ala Ala Ala Ile Ala Tyr 115 120 125 Gly Leu Asp Arg Thr Gly Lys Gly Glu Arg Asn Val Leu Ile Phe Asp 130 135 140 Leu Gly Gly Gly Thr Phe Asp Val Ser Ile Leu Thr Ile Asp Asp Gly 145 150 155 160 Ile Phe Glu Val Lys Ala Thr Ala Gly Asp Thr His Leu Gly Gly Glu 165 170 175 Asp Phe Asp Asn Arg Leu Val Asn His Phe Val Glu Glu Phe Lys Arg 180 185 190 Lys His Lys Lys Asp Ile Ser Gln Asn Lys Arg Ala Val Arg Arg Leu 195 200 205 Arg Thr Ala Cys Glu Arg Ala Lys Arg Thr Leu Ser Ser Ser Thr Gln 210 215 220 Ala Ser Leu Glu Ile Asp Ser Leu Phe Glu Gly Ile Asp Phe Tyr Thr 225 230 235 240 Ser Ile Thr Arg Ala Arg Phe Glu Glu Leu Cys Ser Asp Leu Phe Arg 245 250 255 Ser Thr Leu Glu Pro Val Glu Lys Ala Leu Arg Asp Ala Lys Leu Asp 260 265 270 Lys Ala Gln Ile His Asp Leu Val Leu Val Gly Gly Ser Thr Arg Ile 275 280 285 Pro Lys Val Gln Lys Leu Leu Gln Asp Phe Phe Asp Gly Arg Asp Leu 290 295 300 Asn Lys Ser Ile Asn Pro Asp Glu Ala Val Ala Tyr Gly Ala Ala Val 305 310 315 320 Gln Ala Ala Ile Leu Met Gly Asp Lys Ser Glu Asn Val Gln Asp Leu 325 330 335 Leu Leu Leu Asp Val Ala Pro Leu Ser Leu Gly Leu Glu Thr Ala Gly 340 345 350 Gly Val Met Thr Ala Leu Ile Lys Arg Asn Ser Thr Ile Pro Thr Lys 355 360 365 Gln Thr Gln Ile Phe Thr Thr Tyr Ser Asp Asn Gln Pro Gly Val Leu 370 375 380 Ile Gln Val Tyr Glu Gly Glu Arg Ala Met Thr Lys Asp Asn Asn Leu 385 390 395 400 Leu Gly Arg Phe Glu Leu Ser Gly Ile Pro Pro Ala Pro Arg Gly Val 405 410 415 Pro Gln Ile Glu Val Thr Phe Asp Ile Asp Ala Asn Gly Ile Leu Asn 420 425 430 Val Thr Ala Thr Asp Lys Ser Thr Gly Asn Ala Asn Lys Ile Thr Ile 435 440 445 Thr Asn Asp Lys Gly Arg Leu Ser Lys Glu Glu Ile Glu Arg Met Val 450 455 460 Gln Glu Ala Glu Lys Tyr Lys Ala Glu Asp Glu Val Gln Arg Glu Arg 465 470 475 480 Val Ser Ala Lys Asn Ala Leu Glu Ser Tyr Ala Phe Asn Met Lys Ser 485 490 495 Ala Val Glu Asp Glu Gly Leu Lys Gly Lys Ile Ser Glu Ala Asp Lys 500 505 510 Lys Lys Val Leu Asp Lys Cys Gln Glu Val Ile Ser Trp Leu Asp Ala 515 520 525 Asn Thr Leu Ala Glu Lys Asp Glu Phe Glu His Lys Arg Lys Glu Leu 530 535 540 Glu Gln Val Cys Asn Pro Ile Ile Ser Gly Leu Tyr Gln Gly Ala Gly 545 550 555 560 Gly Pro Gly Pro Gly Gly Phe Gly Ala Gln Gly Pro Lys Gly Gly Ser 565 570 575 Gly Ser Gly Pro Thr Ile Glu Glu Val Asp 580 585 75432PRTHomo sapiens 75Met Thr Thr Ser Ile Arg Gln Phe Thr Ser Ser Ser Ser Ile Lys Gly 1 5 10 15 Ser Ser Gly Leu Gly Gly Gly Ser Ser Arg Thr Ser Cys Arg Leu Ser 20 25 30 Gly Gly Leu Gly Ala Gly Ser Cys Arg Leu Gly Ser Ala Gly Gly Leu 35 40 45 Gly Ser Thr Leu Gly Gly Ser Ser Tyr Ser Ser Cys Tyr Ser Phe Gly 50 55 60 Ser Gly Gly Gly Tyr Gly Ser Ser Phe Gly Gly Val Asp Gly Leu Leu 65 70 75 80 Ala Gly Gly Glu Lys Ala Thr Met Gln Asn Leu Asn Asp Arg Leu Ala 85 90 95 Ser Tyr Leu Asp Lys Val Arg Ala Leu Glu Glu Ala Asn Thr Glu Leu 100 105 110 Glu Val Lys Ile Arg Asp Trp Tyr Gln Arg Gln Ala Pro Gly Pro Ala 115 120 125 Arg Asp Tyr Ser Gln Tyr Tyr Arg Thr Ile Glu Glu Leu Gln Asn Lys 130 135 140 Ile Leu Thr Ala Thr Val Asp Asn Ala Asn Ile Leu Leu Gln Ile Asp 145 150 155 160 Asn Ala Arg Leu Ala Ala Asp Asp Phe Arg Thr Lys Phe Glu Thr Glu 165 170 175 Gln Ala Leu Arg Leu Ser Val Glu Ala Asp Ile Asn Gly Leu Arg Arg 180 185 190 Val Leu Asp Glu Leu Thr Leu Ala Arg Ala Asp Leu Glu Met Gln Ile 195 200 205 Glu Asn Leu Lys Glu Glu Leu Ala Tyr Leu Lys Lys Asn His Glu Glu 210 215 220 Glu Met Asn Ala Leu Arg Gly Gln Val Gly Gly Glu Ile Asn Val Glu 225 230 235 240 Met Asp Ala Ala Pro Gly Val Asp Leu Ser Arg Ile Leu Asn Glu Met 245 250 255 Arg Asp Gln Tyr Glu Lys Met Ala Glu Lys Asn Arg Lys Asp Ala Glu 260 265 270 Asp Trp Phe Phe Ser Lys Thr Glu Glu Leu Asn Arg Glu Val Ala Thr 275 280 285 Asn Ser Glu Leu Val Gln Ser Gly Lys Ser Glu Ile Ser Glu Leu Arg 290 295 300 Arg Thr Met Gln Ala Leu Glu Ile Glu Leu Gln Ser Gln Leu Ser Met 305 310 315 320 Lys Ala Ser Leu Glu Gly Asn Leu Ala Glu Thr Glu Asn Arg Tyr Cys 325 330 335 Val Gln Leu Ser Gln Ile Gln Gly Leu Ile Gly Ser Val Glu Glu Gln 340 345 350 Leu Ala Gln Leu Arg Cys Glu Met Glu Gln Gln Asn Gln Glu Tyr Lys 355 360 365 Ile Leu Leu Asp Val Lys Thr Arg Leu Glu Gln Glu Ile Ala Thr Tyr 370 375 380 Arg Arg Leu Leu Glu Gly Glu Asp Ala His Leu Thr Gln Tyr Lys Lys 385 390 395 400 Glu Pro Val Thr Thr Arg Gln Val Arg Thr Ile Val Glu Glu Val Gln 405 410 415 Asp Gly Lys Val Ile Ser Ser Arg Glu Gln Val His Gln Thr Thr Arg 420 425 430 76205PRTHomo sapiens 76Met Thr Glu Arg Arg Val Pro Phe Ser Leu Leu Arg Gly Pro Ser Trp 1 5 10 15 Asp Pro Phe Arg Asp Trp Tyr Pro His Ser Arg Leu Phe Asp Gln Ala 20 25 30 Phe Gly Leu Pro Arg Leu Pro Glu Glu Trp Ser Gln Trp Leu Gly Gly 35 40 45 Ser Ser Trp Pro Gly Tyr Val Arg Pro Leu Pro Pro Ala Ala Ile Glu 50 55 60 Ser Pro Ala Val Ala Ala Pro Ala Tyr Ser Arg Ala Leu Ser Arg Gln 65 70 75 80 Leu Ser Ser Gly Val Ser Glu Ile Arg His Thr Ala Asp Arg Trp Arg 85 90 95 Val Ser Leu Asp Val Asn His Phe Ala Pro Asp Glu Leu Thr Val Lys 100 105 110 Thr Lys Asp Gly Val Val Glu Ile Thr Gly Lys His Glu Glu Arg Gln 115 120 125 Asp Glu His Gly Tyr Ile Ser Arg Cys Phe Thr Arg Lys Tyr Thr Leu 130 135 140 Pro Pro Gly Val Asp Pro Thr Gln Val Ser Ser Ser Leu Ser Pro Glu 145 150 155 160 Gly Thr Leu Thr Val Glu Ala Pro Met Pro Lys Leu Ala Thr Gln Ser 165 170 175 Asn Glu Ile Thr Ile Pro Val Thr Phe Glu Ser Arg Ala Gln Leu Gly 180 185 190 Gly Pro Glu Ala Ala Lys Ser Asp Glu Thr Ala Ala Lys 195 200 205 772511PRTHomo sapiens 77Met Glu Glu Val Val Ile Ala Gly Met Ser Gly Lys Leu Pro Glu Ser 1 5 10 15 Glu Asn Leu Gln Glu Phe Trp Asp Asn Leu Ile Gly Gly Val Asp Met 20 25 30 Val Thr Asp Asp Asp Arg Arg Trp Lys Ala Gly Leu Tyr Gly Leu Pro 35 40 45 Arg Arg Ser Gly Lys Leu Lys Asp Leu Ser Arg Phe Asp Ala Ser Phe 50 55 60 Phe Gly Val His Pro Lys Gln Ala His Thr Met Asp Pro Gln Leu Arg 65 70 75 80 Leu Leu Leu Glu Val Thr Tyr Glu Ala Ile Val Asp Gly Gly Ile Asn 85 90 95 Pro Asp Ser Leu Arg Gly Thr His Thr Gly Val Trp Val Gly Val Ser 100 105 110 Gly Ser Glu Thr Ser Glu Ala Leu Ser Arg Asp Pro Glu Thr Leu Val 115 120 125 Gly Tyr Ser Met Val Gly Cys Gln Arg Ala Met Met Ala Asn Arg Leu 130 135 140 Ser Phe Phe Phe Asp Phe Arg Gly Pro Ser Ile Ala Leu Asp Thr Ala 145 150 155 160 Cys Ser Ser Ser Leu Met Ala Leu Gln Asn Ala Tyr Gln Ala Ile His 165 170 175 Ser Gly Gln Cys Pro Ala Ala Ile Val Gly Gly Ile Asn Val Leu Leu 180 185 190 Lys Pro Asn Thr Ser Val Gln Phe Leu Arg Leu Gly Met Leu Ser Pro 195 200 205 Glu Gly Thr Cys Lys Ala Phe Asp Thr Ala Gly Asn Gly Tyr Cys Arg 210 215 220 Ser Glu Gly Val Val Ala Val Leu Leu Thr Lys Lys Ser Leu Ala Arg 225 230 235 240 Arg Val Tyr Ala Thr Ile Leu Asn Ala Gly Thr Asn Thr Asp Gly Phe 245 250 255 Lys Glu Gln Gly Val Thr Phe Pro Ser Gly Asp Ile Gln Glu Gln Leu 260 265 270 Ile Arg Ser Leu Tyr Gln Ser Ala Gly Val Ala Pro Glu Ser Phe Glu 275 280 285 Tyr Ile Glu Ala His Gly Thr Gly Thr Lys Val Gly Asp Pro Gln Glu 290 295 300 Leu Asn Gly Ile Thr Arg Ala Leu Cys Ala Thr Arg Gln Glu Pro Leu 305 310 315 320 Leu Ile Gly Ser Thr Lys Ser Asn Met Gly His Pro Glu Pro Ala Ser 325 330 335 Gly Leu Ala Ala Leu Ala Lys Val Leu Leu Ser Leu Glu His Gly Leu 340 345 350 Trp Ala Pro Asn Leu His Phe His Ser Pro Asn Pro Glu Ile Pro Ala 355 360 365 Leu Leu Asp Gly Arg Leu Gln Val Val Asp Gln Pro Leu Pro Val Arg 370 375 380 Gly Gly Asn Val Gly Ile Asn Ser Phe Gly Phe Gly Gly Ser Asn Val 385 390 395 400 His Ile Ile Leu Arg Pro Asn Thr Gln Pro Pro Pro Ala Pro Ala Pro 405 410 415 His Ala Thr Leu Pro Arg Leu Leu Arg Ala Ser Gly Arg Thr Pro Glu 420 425 430 Ala Val Gln Lys Leu Leu Glu Gln Gly Leu Arg His Ser Gln Asp Leu 435 440 445 Ala Phe Leu Ser Met Leu Asn Asp Ile Ala Ala Val Pro Ala Thr Ala 450 455 460 Met Pro Phe Arg Gly Tyr Ala Val Leu Gly Gly Glu Arg Gly Gly Pro 465 470 475 480 Glu Val Gln Gln Val Pro Ala Gly Glu Arg Pro Leu Trp Phe Ile Cys 485 490 495 Ser Gly Met Gly Thr Gln Trp Arg Gly Met Gly Leu Ser Leu Met Arg 500 505

510 Leu Asp Arg Phe Arg Asp Ser Ile Leu Arg Ser Asp Glu Ala Val Lys 515 520 525 Pro Phe Gly Leu Lys Val Ser Gln Leu Leu Leu Ser Thr Asp Glu Ser 530 535 540 Thr Phe Asp Asp Ile Val His Ser Phe Val Ser Leu Thr Ala Ile Gln 545 550 555 560 Ile Gly Leu Ile Asp Leu Leu Ser Cys Met Gly Leu Arg Pro Asp Gly 565 570 575 Ile Val Gly His Ser Leu Gly Glu Val Ala Cys Gly Tyr Ala Asp Gly 580 585 590 Cys Leu Ser Gln Glu Glu Ala Val Leu Ala Ala Tyr Trp Arg Gly Gln 595 600 605 Cys Ile Lys Glu Ala His Leu Pro Pro Gly Ala Met Ala Ala Val Gly 610 615 620 Leu Ser Trp Glu Glu Cys Lys Gln Arg Cys Pro Pro Gly Val Val Pro 625 630 635 640 Ala Cys His Asn Ser Lys Asp Thr Val Thr Ile Ser Gly Pro Gln Ala 645 650 655 Pro Val Phe Glu Phe Val Glu Gln Leu Arg Lys Glu Gly Val Phe Ala 660 665 670 Lys Glu Val Arg Thr Gly Gly Met Ala Phe His Ser Tyr Phe Met Glu 675 680 685 Ala Ile Ala Pro Pro Leu Leu Gln Glu Leu Lys Lys Val Ile Arg Glu 690 695 700 Pro Lys Pro Arg Ser Ala Arg Trp Leu Ser Thr Ser Ile Pro Glu Ala 705 710 715 720 Gln Trp His Ser Ser Leu Ala Arg Thr Ser Ser Ala Glu Tyr Asn Val 725 730 735 Asn Asn Leu Val Ser Pro Val Leu Phe Gln Glu Ala Leu Trp His Val 740 745 750 Pro Glu His Ala Val Val Leu Glu Ile Ala Pro His Ala Leu Leu Gln 755 760 765 Ala Val Leu Lys Arg Gly Leu Lys Pro Ser Cys Thr Ile Ile Pro Leu 770 775 780 Met Lys Lys Asp His Arg Asp Asn Leu Glu Phe Phe Leu Ala Gly Ile 785 790 795 800 Gly Arg Leu His Leu Ser Gly Ile Asp Ala Asn Pro Asn Ala Leu Phe 805 810 815 Pro Pro Val Glu Phe Pro Ala Pro Arg Gly Thr Pro Leu Ile Ser Pro 820 825 830 Leu Ile Lys Trp Asp His Ser Leu Ala Trp Asp Val Pro Ala Ala Glu 835 840 845 Asp Phe Pro Asn Gly Ser Gly Ser Pro Ser Ala Ala Ile Tyr Asn Ile 850 855 860 Asp Thr Ser Ser Glu Ser Pro Asp His Tyr Leu Val Asp His Thr Leu 865 870 875 880 Asp Gly Arg Val Leu Phe Pro Ala Thr Gly Tyr Leu Ser Ile Val Trp 885 890 895 Lys Thr Leu Ala Arg Ala Leu Gly Leu Gly Val Glu Gln Leu Pro Val 900 905 910 Val Phe Glu Asp Val Val Leu His Gln Ala Thr Ile Leu Pro Lys Thr 915 920 925 Gly Thr Val Ser Leu Glu Val Arg Leu Leu Glu Ala Ser Arg Ala Phe 930 935 940 Glu Val Ser Glu Asn Gly Asn Leu Val Val Ser Gly Lys Val Tyr Gln 945 950 955 960 Trp Asp Asp Pro Asp Pro Arg Leu Phe Asp His Pro Glu Ser Pro Thr 965 970 975 Pro Asn Pro Thr Glu Pro Leu Phe Leu Ala Gln Ala Glu Val Tyr Lys 980 985 990 Glu Leu Arg Leu Arg Gly Tyr Asp Tyr Gly Pro His Phe Gln Gly Ile 995 1000 1005 Leu Glu Ala Ser Leu Glu Gly Asp Ser Gly Arg Leu Leu Trp Lys 1010 1015 1020 Asp Asn Trp Val Ser Phe Met Asp Thr Met Leu Gln Met Ser Ile 1025 1030 1035 Leu Gly Ser Ala Lys His Gly Leu Tyr Leu Pro Thr Arg Val Thr 1040 1045 1050 Ala Ile His Ile Asp Pro Ala Thr His Arg Gln Lys Leu Tyr Thr 1055 1060 1065 Leu Gln Asp Lys Ala Gln Val Ala Asp Val Val Val Ser Arg Trp 1070 1075 1080 Leu Arg Val Thr Val Ala Gly Gly Val His Ile Ser Gly Leu His 1085 1090 1095 Thr Glu Ser Ala Pro Arg Arg Gln Gln Glu Gln Gln Val Pro Ile 1100 1105 1110 Leu Glu Lys Phe Cys Phe Thr Pro His Thr Glu Glu Gly Cys Leu 1115 1120 1125 Ser Glu Arg Ala Ala Leu Gln Glu Glu Leu Gln Leu Cys Lys Gly 1130 1135 1140 Leu Val Gln Ala Leu Gln Thr Lys Val Thr Gln Gln Gly Leu Lys 1145 1150 1155 Met Val Val Pro Gly Leu Asp Gly Ala Gln Ile Pro Arg Asp Pro 1160 1165 1170 Ser Gln Gln Glu Leu Pro Arg Leu Leu Ser Ala Ala Cys Arg Leu 1175 1180 1185 Gln Leu Asn Gly Asn Leu Gln Leu Glu Leu Ala Gln Val Leu Ala 1190 1195 1200 Gln Glu Arg Pro Lys Leu Pro Glu Asp Pro Leu Leu Ser Gly Leu 1205 1210 1215 Leu Asp Ser Pro Ala Leu Lys Ala Cys Leu Asp Thr Ala Val Glu 1220 1225 1230 Asn Met Pro Ser Leu Lys Met Lys Val Val Glu Val Leu Ala Gly 1235 1240 1245 His Gly His Leu Tyr Ser Arg Ile Pro Gly Leu Leu Ser Pro His 1250 1255 1260 Pro Leu Leu Gln Leu Ser Tyr Thr Ala Thr Asp Arg His Pro Gln 1265 1270 1275 Ala Leu Glu Ala Ala Gln Ala Glu Leu Gln Gln His Asp Val Ala 1280 1285 1290 Gln Gly Gln Trp Asp Pro Ala Asp Pro Ala Pro Ser Ala Leu Gly 1295 1300 1305 Ser Ala Asp Leu Leu Val Cys Asn Cys Ala Val Ala Ala Leu Gly 1310 1315 1320 Asp Pro Ala Ser Ala Leu Ser Asn Met Val Ala Ala Leu Arg Glu 1325 1330 1335 Gly Gly Phe Leu Leu Leu His Thr Leu Leu Arg Gly His Pro Leu 1340 1345 1350 Gly Asp Ile Val Ala Phe Leu Thr Ser Thr Glu Pro Gln Tyr Gly 1355 1360 1365 Gln Gly Ile Leu Ser Gln Asp Ala Trp Glu Ser Leu Phe Ser Arg 1370 1375 1380 Val Ser Leu Arg Leu Val Gly Leu Lys Lys Ser Phe Tyr Gly Ser 1385 1390 1395 Thr Leu Phe Leu Cys Arg Arg Pro Thr Pro Gln Asp Ser Pro Ile 1400 1405 1410 Phe Leu Pro Val Asp Asp Thr Ser Phe Arg Trp Val Glu Ser Leu 1415 1420 1425 Lys Gly Ile Leu Ala Asp Glu Asp Ser Ser Arg Pro Val Trp Leu 1430 1435 1440 Lys Ala Ile Asn Cys Ala Thr Ser Gly Val Val Gly Leu Val Asn 1445 1450 1455 Cys Leu Arg Arg Glu Pro Gly Gly Asn Arg Leu Arg Cys Val Leu 1460 1465 1470 Leu Ser Asn Leu Ser Ser Thr Ser His Val Pro Glu Val Asp Pro 1475 1480 1485 Gly Ser Ala Glu Leu Gln Lys Val Leu Gln Gly Asp Leu Val Met 1490 1495 1500 Asn Val Tyr Arg Asp Gly Ala Trp Gly Ala Phe Arg His Phe Leu 1505 1510 1515 Leu Glu Glu Asp Lys Pro Glu Glu Pro Thr Ala His Ala Phe Val 1520 1525 1530 Ser Thr Leu Thr Arg Gly Asp Leu Ser Ser Ile Arg Trp Val Cys 1535 1540 1545 Ser Ser Leu Arg His Ala Gln Pro Thr Cys Pro Gly Ala Gln Leu 1550 1555 1560 Cys Thr Val Tyr Tyr Ala Ser Leu Asn Phe Arg Asp Ile Met Leu 1565 1570 1575 Ala Thr Gly Lys Leu Ser Pro Asp Ala Ile Pro Gly Lys Trp Thr 1580 1585 1590 Ser Gln Asp Ser Leu Leu Gly Met Glu Phe Ser Gly Arg Asp Ala 1595 1600 1605 Ser Gly Lys Arg Val Met Gly Leu Val Pro Ala Lys Gly Leu Ala 1610 1615 1620 Thr Ser Val Leu Leu Ser Pro Asp Phe Leu Trp Asp Val Pro Ser 1625 1630 1635 Asn Trp Thr Leu Glu Glu Ala Ala Ser Val Pro Val Val Tyr Ser 1640 1645 1650 Thr Ala Tyr Tyr Ala Leu Val Val Arg Gly Arg Val Arg Pro Gly 1655 1660 1665 Glu Thr Leu Leu Ile His Ser Gly Ser Gly Gly Val Gly Gln Ala 1670 1675 1680 Ala Ile Ala Ile Ala Leu Ser Leu Gly Cys Arg Val Phe Thr Thr 1685 1690 1695 Val Gly Ser Ala Glu Lys Arg Ala Tyr Leu Gln Ala Arg Phe Pro 1700 1705 1710 Gln Leu Asp Ser Thr Ser Phe Ala Asn Ser Arg Asp Thr Ser Phe 1715 1720 1725 Glu Gln His Val Leu Trp His Thr Gly Gly Lys Gly Val Asp Leu 1730 1735 1740 Val Leu Asn Ser Leu Ala Glu Glu Lys Leu Gln Ala Ser Val Arg 1745 1750 1755 Cys Leu Ala Thr His Gly Arg Phe Leu Glu Ile Gly Lys Phe Asp 1760 1765 1770 Leu Ser Gln Asn His Pro Leu Gly Met Ala Ile Phe Leu Lys Asn 1775 1780 1785 Val Thr Phe His Gly Val Leu Leu Asp Ala Phe Phe Asn Glu Ser 1790 1795 1800 Ser Ala Asp Trp Arg Glu Val Trp Ala Leu Val Gln Ala Gly Ile 1805 1810 1815 Arg Asp Gly Val Val Arg Pro Leu Lys Cys Thr Val Phe His Gly 1820 1825 1830 Ala Gln Val Glu Asp Ala Phe Arg Tyr Met Ala Gln Gly Lys His 1835 1840 1845 Ile Gly Lys Val Val Val Gln Val Leu Ala Glu Glu Pro Glu Ala 1850 1855 1860 Val Leu Lys Gly Ala Lys Pro Lys Leu Met Ser Ala Ile Ser Lys 1865 1870 1875 Thr Phe Cys Pro Ala His Lys Ser Tyr Ile Ile Ala Gly Gly Leu 1880 1885 1890 Gly Gly Phe Gly Leu Glu Leu Ala Gln Trp Leu Ile Gln Arg Gly 1895 1900 1905 Val Gln Lys Leu Val Leu Thr Ser Arg Ser Gly Ile Arg Thr Gly 1910 1915 1920 Tyr Gln Ala Lys Gln Val Arg Arg Trp Arg Arg Gln Gly Val Gln 1925 1930 1935 Val Gln Val Ser Thr Ser Asn Ile Ser Ser Leu Glu Gly Ala Arg 1940 1945 1950 Gly Leu Ile Ala Glu Ala Ala Gln Leu Gly Pro Val Gly Gly Val 1955 1960 1965 Phe Asn Leu Ala Val Val Leu Arg Asp Gly Leu Leu Glu Asn Gln 1970 1975 1980 Thr Pro Glu Phe Phe Gln Asp Val Cys Lys Pro Lys Tyr Ser Gly 1985 1990 1995 Thr Leu Asn Leu Asp Arg Val Thr Arg Glu Ala Cys Pro Glu Leu 2000 2005 2010 Asp Tyr Phe Val Val Phe Ser Ser Val Ser Cys Gly Arg Gly Asn 2015 2020 2025 Ala Gly Gln Ser Asn Tyr Gly Phe Ala Asn Ser Ala Met Glu Arg 2030 2035 2040 Ile Cys Glu Lys Arg Arg His Glu Gly Leu Pro Gly Leu Ala Val 2045 2050 2055 Gln Trp Gly Ala Ile Gly Asp Val Gly Ile Leu Val Glu Thr Met 2060 2065 2070 Ser Thr Asn Asp Thr Ile Val Ser Gly Thr Leu Pro Gln Arg Met 2075 2080 2085 Ala Ser Cys Leu Glu Val Leu Asp Leu Phe Leu Asn Gln Pro His 2090 2095 2100 Met Val Leu Ser Ser Phe Val Leu Ala Glu Lys Ala Ala Ala Tyr 2105 2110 2115 Arg Asp Arg Asp Ser Gln Arg Asp Leu Val Glu Ala Val Ala His 2120 2125 2130 Ile Leu Gly Ile Arg Asp Leu Ala Ala Val Asn Leu Asp Ser Ser 2135 2140 2145 Leu Ala Asp Leu Gly Leu Asp Ser Leu Met Ser Val Glu Val Arg 2150 2155 2160 Gln Thr Leu Glu Arg Glu Leu Asn Leu Val Leu Ser Val Arg Glu 2165 2170 2175 Val Arg Gln Leu Thr Leu Arg Lys Leu Gln Glu Leu Ser Ser Lys 2180 2185 2190 Ala Asp Glu Ala Ser Glu Leu Ala Cys Pro Thr Pro Lys Glu Asp 2195 2200 2205 Gly Leu Ala Gln Gln Gln Thr Gln Leu Asn Leu Arg Ser Leu Leu 2210 2215 2220 Val Asn Pro Glu Gly Pro Thr Leu Met Arg Leu Asn Ser Val Gln 2225 2230 2235 Ser Ser Glu Arg Pro Leu Phe Leu Val His Pro Ile Glu Gly Ser 2240 2245 2250 Thr Thr Val Phe His Ser Leu Ala Ser Arg Leu Ser Ile Pro Thr 2255 2260 2265 Tyr Gly Leu Gln Cys Thr Arg Ala Ala Pro Leu Asp Ser Ile His 2270 2275 2280 Ser Leu Ala Ala Tyr Tyr Ile Asp Cys Ile Arg Gln Val Gln Pro 2285 2290 2295 Glu Gly Pro Tyr Arg Val Ala Gly Tyr Ser Tyr Gly Ala Cys Val 2300 2305 2310 Ala Phe Glu Met Cys Ser Gln Leu Gln Ala Gln Gln Ser Pro Ala 2315 2320 2325 Pro Thr His Asn Ser Leu Phe Leu Phe Asp Gly Ser Pro Thr Tyr 2330 2335 2340 Val Leu Ala Tyr Thr Gln Ser Tyr Arg Ala Lys Leu Thr Pro Gly 2345 2350 2355 Cys Glu Ala Glu Ala Glu Thr Glu Ala Ile Cys Phe Phe Val Gln 2360 2365 2370 Gln Phe Thr Asp Met Glu His Asn Arg Val Leu Glu Ala Leu Leu 2375 2380 2385 Pro Leu Lys Gly Leu Glu Glu Arg Val Ala Ala Ala Val Asp Leu 2390 2395 2400 Ile Ile Lys Ser His Gln Gly Leu Asp Arg Gln Glu Leu Ser Phe 2405 2410 2415 Ala Ala Arg Ser Phe Tyr Tyr Lys Leu Arg Ala Ala Glu Gln Tyr 2420 2425 2430 Thr Pro Lys Ala Lys Tyr His Gly Asn Val Met Leu Leu Arg Ala 2435 2440 2445 Lys Thr Gly Gly Ala Tyr Gly Glu Asp Leu Gly Ala Asp Tyr Asn 2450 2455 2460 Leu Ser Gln Val Cys Asp Gly Lys Val Ser Val His Val Ile Glu 2465 2470 2475 Gly Asp His Arg Thr Leu Leu Glu Gly Ser Gly Leu Glu Ser Ile 2480 2485 2490 Ile Ser Ile Ile His Ser Ser Leu Ala Glu Pro Arg Val Ser Val 2495 2500 2505 Arg Glu Gly 2510 78564PRTHomo sapiens 78Met Ala Ser Thr Ser Thr Thr Ile Arg Ser His Ser Ser Ser Arg Arg 1 5 10 15 Gly Phe Ser Ala Asn Ser Ala Arg Leu Pro Gly Val Ser Arg Ser Gly 20 25 30 Phe Ser Ser Val Ser Val Ser Arg Ser Arg Gly Ser Gly Gly Leu Gly 35 40 45 Gly Ala Cys Gly Gly Ala Gly Phe Gly Ser Arg Ser Leu Tyr Gly Leu 50 55 60 Gly Gly Ser Lys Arg Ile Ser Ile Gly Gly Gly Ser Cys Ala Ile Ser 65 70 75 80 Gly Gly Tyr Gly Ser Arg Ala Gly Gly Ser Tyr Gly Phe Gly Gly Ala 85 90 95 Gly Ser Gly Phe Gly Phe Gly Gly Gly Ala Gly Ile Gly Phe Gly Leu 100 105 110 Gly Gly Gly Ala Gly Leu Ala Gly Gly Phe Gly Gly Pro Gly Phe Pro 115 120 125 Val Cys Pro Pro Gly Gly Ile Gln Glu Val Thr Val Asn Gln Ser Leu 130 135 140 Leu Thr Pro Leu Asn Leu Gln Ile Asp Pro Thr Ile Gln Arg Val Arg 145 150 155 160 Ala Glu Glu Arg Glu Gln Ile Lys Thr Leu Asn Asn Lys Phe Ala Ser 165 170 175 Phe Ile Asp Lys Val Arg Phe Leu Glu Gln Gln Asn Lys Val Leu Glu 180 185 190 Thr Lys Trp Thr Leu Leu Gln Glu Gln Gly Thr Lys Thr Val Arg Gln 195 200 205 Asn Leu Glu Pro Leu Phe Glu Gln Tyr Ile Asn Asn Leu Arg Arg Gln 210 215 220

Leu Asp Ser Ile Val Gly Glu Arg Gly Arg Leu Asp Ser Glu Leu Arg 225 230 235 240 Gly Met Gln Asp Leu Val Glu Asp Phe Lys Asn Lys Tyr Glu Asp Glu 245 250 255 Ile Asn Lys Arg Thr Ala Ala Glu Asn Glu Phe Val Thr Leu Lys Lys 260 265 270 Asp Val Asp Ala Ala Tyr Met Asn Lys Val Glu Leu Gln Ala Lys Ala 275 280 285 Asp Thr Leu Thr Asp Glu Ile Asn Phe Leu Arg Ala Leu Tyr Asp Ala 290 295 300 Glu Leu Ser Gln Met Gln Thr His Ile Ser Asp Thr Ser Val Val Leu 305 310 315 320 Ser Met Asp Asn Asn Arg Asn Leu Asp Leu Asp Ser Ile Ile Ala Glu 325 330 335 Val Lys Ala Gln Tyr Glu Glu Ile Ala Gln Arg Ser Arg Ala Glu Ala 340 345 350 Glu Ser Trp Tyr Gln Thr Lys Tyr Glu Glu Leu Gln Val Thr Ala Gly 355 360 365 Arg His Gly Asp Asp Leu Arg Asn Thr Lys Gln Glu Ile Ala Glu Ile 370 375 380 Asn Arg Met Ile Gln Arg Leu Arg Ser Glu Ile Asp His Val Lys Lys 385 390 395 400 Gln Cys Ala Asn Leu Gln Ala Ala Ile Ala Asp Ala Glu Gln Arg Gly 405 410 415 Glu Met Ala Leu Lys Asp Ala Lys Asn Lys Leu Glu Gly Leu Glu Asp 420 425 430 Ala Leu Gln Lys Ala Lys Gln Asp Leu Ala Arg Leu Leu Lys Glu Tyr 435 440 445 Gln Glu Leu Met Asn Val Lys Leu Ala Leu Asp Val Glu Ile Ala Thr 450 455 460 Tyr Arg Lys Leu Leu Glu Gly Glu Glu Cys Arg Leu Asn Gly Glu Gly 465 470 475 480 Val Gly Gln Val Asn Ile Ser Val Val Gln Ser Thr Val Ser Ser Gly 485 490 495 Tyr Gly Gly Ala Ser Gly Val Gly Ser Gly Leu Gly Leu Gly Gly Gly 500 505 510 Ser Ser Tyr Ser Tyr Gly Ser Gly Leu Gly Val Gly Gly Gly Phe Ser 515 520 525 Ser Ser Ser Gly Arg Ala Ile Gly Gly Gly Leu Ser Ser Val Gly Gly 530 535 540 Gly Ser Ser Thr Ile Lys Tyr Thr Thr Thr Ser Ser Ser Ser Arg Lys 545 550 555 560 Ser Tyr Lys His 792871PRTHomo sapiens 79Met Ser Cys Asn Gly Gly Ser His Pro Arg Ile Asn Thr Leu Gly Arg 1 5 10 15 Met Ile Arg Ala Glu Ser Gly Pro Asp Leu Arg Tyr Glu Val Thr Ser 20 25 30 Gly Gly Gly Gly Thr Ser Arg Met Tyr Tyr Ser Arg Arg Gly Val Ile 35 40 45 Thr Asp Gln Asn Ser Asp Gly Tyr Cys Gln Thr Gly Thr Met Ser Arg 50 55 60 His Gln Asn Gln Asn Thr Ile Gln Glu Leu Leu Gln Asn Cys Ser Asp 65 70 75 80 Cys Leu Met Arg Ala Glu Leu Ile Val Gln Pro Glu Leu Lys Tyr Gly 85 90 95 Asp Gly Ile Gln Leu Thr Arg Ser Arg Glu Leu Asp Glu Cys Phe Ala 100 105 110 Gln Ala Asn Asp Gln Met Glu Ile Leu Asp Ser Leu Ile Arg Glu Met 115 120 125 Arg Gln Met Gly Gln Pro Cys Asp Ala Tyr Gln Lys Arg Leu Leu Gln 130 135 140 Leu Gln Glu Gln Met Arg Ala Leu Tyr Lys Ala Ile Ser Val Pro Arg 145 150 155 160 Val Arg Arg Ala Ser Ser Lys Gly Gly Gly Gly Tyr Thr Cys Gln Ser 165 170 175 Gly Ser Gly Trp Asp Glu Phe Thr Lys His Val Thr Ser Glu Cys Leu 180 185 190 Gly Trp Met Arg Gln Gln Arg Ala Glu Met Asp Met Val Ala Trp Gly 195 200 205 Val Asp Leu Ala Ser Val Glu Gln His Ile Asn Ser His Arg Gly Ile 210 215 220 His Asn Ser Ile Gly Asp Tyr Arg Trp Gln Leu Asp Lys Ile Lys Ala 225 230 235 240 Asp Leu Arg Glu Lys Ser Ala Ile Tyr Gln Leu Glu Glu Glu Tyr Glu 245 250 255 Asn Leu Leu Lys Ala Ser Phe Glu Arg Met Asp His Leu Arg Gln Leu 260 265 270 Gln Asn Ile Ile Gln Ala Thr Ser Arg Glu Ile Met Trp Ile Asn Asp 275 280 285 Cys Glu Glu Glu Glu Leu Leu Tyr Asp Trp Ser Asp Lys Asn Thr Asn 290 295 300 Ile Ala Gln Lys Gln Glu Ala Phe Ser Ile Arg Met Ser Gln Leu Glu 305 310 315 320 Val Lys Glu Lys Glu Leu Asn Lys Leu Lys Gln Glu Ser Asp Gln Leu 325 330 335 Val Leu Asn Gln His Pro Ala Ser Asp Lys Ile Glu Ala Tyr Met Asp 340 345 350 Thr Leu Gln Thr Gln Trp Ser Trp Ile Leu Gln Ile Thr Lys Cys Ile 355 360 365 Asp Val His Leu Lys Glu Asn Ala Ala Tyr Phe Gln Phe Phe Glu Glu 370 375 380 Ala Gln Ser Thr Glu Ala Tyr Leu Lys Gly Leu Gln Asp Ser Ile Arg 385 390 395 400 Lys Lys Tyr Pro Cys Asp Lys Asn Met Pro Leu Gln His Leu Leu Glu 405 410 415 Gln Ile Lys Glu Leu Glu Lys Glu Arg Glu Lys Ile Leu Glu Tyr Lys 420 425 430 Arg Gln Val Gln Asn Leu Val Asn Lys Ser Lys Lys Ile Val Gln Leu 435 440 445 Lys Pro Arg Asn Pro Asp Tyr Arg Ser Asn Lys Pro Ile Ile Leu Arg 450 455 460 Ala Leu Cys Asp Tyr Lys Gln Asp Gln Lys Ile Val His Lys Gly Asp 465 470 475 480 Glu Cys Ile Leu Lys Asp Asn Asn Glu Arg Ser Lys Trp Tyr Val Thr 485 490 495 Gly Pro Gly Gly Val Asp Met Leu Val Pro Ser Val Gly Leu Ile Ile 500 505 510 Pro Pro Pro Asn Pro Leu Ala Val Asp Leu Ser Cys Lys Ile Glu Gln 515 520 525 Tyr Tyr Glu Ala Ile Leu Ala Leu Trp Asn Gln Leu Tyr Ile Asn Met 530 535 540 Lys Ser Leu Val Ser Trp His Tyr Cys Met Ile Asp Ile Glu Lys Ile 545 550 555 560 Arg Ala Met Thr Ile Ala Lys Leu Lys Thr Met Arg Gln Glu Asp Tyr 565 570 575 Met Lys Thr Ile Ala Asp Leu Glu Leu His Tyr Gln Glu Phe Ile Arg 580 585 590 Asn Ser Gln Gly Ser Glu Met Phe Gly Asp Asp Asp Lys Arg Lys Ile 595 600 605 Gln Ser Gln Phe Thr Asp Ala Gln Lys His Tyr Gln Thr Leu Val Ile 610 615 620 Gln Leu Pro Gly Tyr Pro Gln His Gln Thr Val Thr Thr Thr Glu Ile 625 630 635 640 Thr His His Gly Thr Cys Gln Asp Val Asn His Asn Lys Val Ile Glu 645 650 655 Thr Asn Arg Glu Asn Asp Lys Gln Glu Thr Trp Met Leu Met Glu Leu 660 665 670 Gln Lys Ile Arg Arg Gln Ile Glu His Cys Glu Gly Arg Met Thr Leu 675 680 685 Lys Asn Leu Pro Leu Ala Asp Gln Gly Ser Ser His His Ile Thr Val 690 695 700 Lys Ile Asn Glu Leu Lys Ser Val Gln Asn Asp Ser Gln Ala Ile Ala 705 710 715 720 Glu Val Leu Asn Gln Leu Lys Asp Met Leu Ala Asn Phe Arg Gly Ser 725 730 735 Glu Lys Tyr Cys Tyr Leu Gln Asn Glu Val Phe Gly Leu Phe Gln Lys 740 745 750 Leu Glu Asn Ile Asn Gly Val Thr Asp Gly Tyr Leu Asn Ser Leu Cys 755 760 765 Thr Val Arg Ala Leu Leu Gln Ala Ile Leu Gln Thr Glu Asp Met Leu 770 775 780 Lys Val Tyr Glu Ala Arg Leu Thr Glu Glu Glu Thr Val Cys Leu Asp 785 790 795 800 Leu Asp Lys Val Glu Ala Tyr Arg Cys Gly Leu Lys Lys Ile Lys Asn 805 810 815 Asp Leu Asn Leu Lys Lys Ser Leu Leu Ala Thr Met Lys Thr Glu Leu 820 825 830 Gln Lys Ala Gln Gln Ile His Ser Gln Thr Ser Gln Gln Tyr Pro Leu 835 840 845 Tyr Asp Leu Asp Leu Gly Lys Phe Gly Glu Lys Val Thr Gln Leu Thr 850 855 860 Asp Arg Trp Gln Arg Ile Asp Lys Gln Ile Asp Phe Arg Leu Trp Asp 865 870 875 880 Leu Glu Lys Gln Ile Lys Gln Leu Arg Asn Tyr Arg Asp Asn Tyr Gln 885 890 895 Ala Phe Cys Lys Trp Leu Tyr Asp Ala Lys Arg Arg Gln Asp Ser Leu 900 905 910 Glu Ser Met Lys Phe Gly Asp Ser Asn Thr Val Met Arg Phe Leu Asn 915 920 925 Glu Gln Lys Asn Leu His Ser Glu Ile Ser Gly Lys Arg Asp Lys Ser 930 935 940 Glu Glu Val Gln Lys Ile Ala Glu Leu Cys Ala Asn Ser Ile Lys Asp 945 950 955 960 Tyr Glu Leu Gln Leu Ala Ser Tyr Thr Ser Gly Leu Glu Thr Leu Leu 965 970 975 Asn Ile Pro Ile Lys Arg Thr Met Ile Gln Ser Pro Ser Gly Val Ile 980 985 990 Leu Gln Glu Ala Ala Asp Val His Ala Arg Tyr Ile Glu Leu Leu Thr 995 1000 1005 Arg Ser Gly Asp Tyr Tyr Arg Phe Leu Ser Glu Met Leu Lys Ser 1010 1015 1020 Leu Glu Asp Leu Lys Leu Lys Asn Thr Lys Ile Glu Val Leu Glu 1025 1030 1035 Glu Glu Leu Arg Leu Ala Arg Asp Ala Asn Ser Glu Asn Cys Asn 1040 1045 1050 Lys Asn Lys Phe Leu Asp Gln Asn Leu Gln Lys Tyr Gln Ala Glu 1055 1060 1065 Cys Ser Gln Phe Lys Ala Lys Leu Ala Ser Leu Glu Glu Leu Lys 1070 1075 1080 Arg Gln Ala Glu Leu Asp Gly Lys Ser Ala Lys Gln Asn Leu Asp 1085 1090 1095 Lys Cys Tyr Gly Gln Ile Lys Glu Leu Asn Glu Lys Ile Thr Arg 1100 1105 1110 Leu Thr Tyr Glu Ile Glu Asp Glu Lys Arg Arg Arg Lys Ser Val 1115 1120 1125 Glu Asp Arg Phe Asp Gln Gln Lys Asn Asp Tyr Asp Gln Leu Gln 1130 1135 1140 Lys Ala Arg Gln Cys Glu Lys Glu Asn Leu Gly Trp Gln Lys Leu 1145 1150 1155 Glu Ser Glu Lys Ala Ile Lys Glu Lys Glu Tyr Glu Ile Glu Arg 1160 1165 1170 Leu Arg Val Leu Leu Gln Glu Glu Gly Thr Arg Lys Arg Glu Tyr 1175 1180 1185 Glu Asn Glu Leu Ala Lys Val Arg Asn His Tyr Asn Glu Glu Met 1190 1195 1200 Ser Asn Leu Arg Asn Lys Tyr Glu Thr Glu Ile Asn Ile Thr Lys 1205 1210 1215 Thr Thr Ile Lys Glu Ile Ser Met Gln Lys Glu Asp Asp Ser Lys 1220 1225 1230 Asn Leu Arg Asn Gln Leu Asp Arg Leu Ser Arg Glu Asn Arg Asp 1235 1240 1245 Leu Lys Asp Glu Ile Val Arg Leu Asn Asp Ser Ile Leu Gln Ala 1250 1255 1260 Thr Glu Gln Arg Arg Arg Ala Glu Glu Asn Ala Leu Gln Gln Lys 1265 1270 1275 Ala Cys Gly Ser Glu Ile Met Gln Lys Lys Gln His Leu Glu Ile 1280 1285 1290 Glu Leu Lys Gln Val Met Gln Gln Arg Ser Glu Asp Asn Ala Arg 1295 1300 1305 His Lys Gln Ser Leu Glu Glu Ala Ala Lys Thr Ile Gln Asp Lys 1310 1315 1320 Asn Lys Glu Ile Glu Arg Leu Lys Ala Glu Phe Gln Glu Glu Ala 1325 1330 1335 Lys Arg Arg Trp Glu Tyr Glu Asn Glu Leu Ser Lys Val Arg Asn 1340 1345 1350 Asn Tyr Asp Glu Glu Ile Ile Ser Leu Lys Asn Gln Phe Glu Thr 1355 1360 1365 Glu Ile Asn Ile Thr Lys Thr Thr Ile His Gln Leu Thr Met Gln 1370 1375 1380 Lys Glu Glu Asp Thr Ser Gly Tyr Arg Ala Gln Ile Asp Asn Leu 1385 1390 1395 Thr Arg Glu Asn Arg Ser Leu Ser Glu Glu Ile Lys Arg Leu Lys 1400 1405 1410 Asn Thr Leu Thr Gln Thr Thr Glu Asn Leu Arg Arg Val Glu Glu 1415 1420 1425 Asp Ile Gln Gln Gln Lys Ala Thr Gly Ser Glu Val Ser Gln Arg 1430 1435 1440 Lys Gln Gln Leu Glu Val Glu Leu Arg Gln Val Thr Gln Met Arg 1445 1450 1455 Thr Glu Glu Ser Val Arg Tyr Lys Gln Ser Leu Asp Asp Ala Ala 1460 1465 1470 Lys Thr Ile Gln Asp Lys Asn Lys Glu Ile Glu Arg Leu Lys Gln 1475 1480 1485 Leu Ile Asp Lys Glu Thr Asn Asp Arg Lys Cys Leu Glu Asp Glu 1490 1495 1500 Asn Ala Arg Leu Gln Arg Val Gln Tyr Asp Leu Gln Lys Ala Asn 1505 1510 1515 Ser Ser Ala Thr Glu Thr Ile Asn Lys Leu Lys Val Gln Glu Gln 1520 1525 1530 Glu Leu Thr Arg Leu Arg Ile Asp Tyr Glu Arg Val Ser Gln Glu 1535 1540 1545 Arg Thr Val Lys Asp Gln Asp Ile Thr Arg Phe Gln Asn Ser Leu 1550 1555 1560 Lys Glu Leu Gln Leu Gln Lys Gln Lys Val Glu Glu Glu Leu Asn 1565 1570 1575 Arg Leu Lys Arg Thr Ala Ser Glu Asp Ser Cys Lys Arg Lys Lys 1580 1585 1590 Leu Glu Glu Glu Leu Glu Gly Met Arg Arg Ser Leu Lys Glu Gln 1595 1600 1605 Ala Ile Lys Ile Thr Asn Leu Thr Gln Gln Leu Glu Gln Ala Ser 1610 1615 1620 Ile Val Lys Lys Arg Ser Glu Asp Asp Leu Arg Gln Gln Arg Asp 1625 1630 1635 Val Leu Asp Gly His Leu Arg Glu Lys Gln Arg Thr Gln Glu Glu 1640 1645 1650 Leu Arg Arg Leu Ser Ser Glu Val Glu Ala Leu Arg Arg Gln Leu 1655 1660 1665 Leu Gln Glu Gln Glu Ser Val Lys Gln Ala His Leu Arg Asn Glu 1670 1675 1680 His Phe Gln Lys Ala Ile Glu Asp Lys Ser Arg Ser Leu Asn Glu 1685 1690 1695 Ser Lys Ile Glu Ile Glu Arg Leu Gln Ser Leu Thr Glu Asn Leu 1700 1705 1710 Thr Lys Glu His Leu Met Leu Glu Glu Glu Leu Arg Asn Leu Arg 1715 1720 1725 Leu Glu Tyr Asp Asp Leu Arg Arg Gly Arg Ser Glu Ala Asp Ser 1730 1735 1740 Asp Lys Asn Ala Thr Ile Leu Glu Leu Arg Ser Gln Leu Gln Ile 1745 1750 1755 Ser Asn Asn Arg Thr Leu Glu Leu Gln Gly Leu Ile Asn Asp Leu 1760 1765 1770 Gln Arg Glu Arg Glu Asn Leu Arg Gln Glu Ile Glu Lys Phe Gln 1775 1780 1785 Lys Gln Ala Leu Glu Ala Ser Asn Arg Ile Gln Glu Ser Lys Asn 1790 1795 1800 Gln Cys Thr Gln Val Val Gln Glu Arg Glu Ser Leu Leu Val Lys 1805 1810 1815 Ile Lys Val Leu Glu Gln Asp Lys Ala Arg Leu Gln Arg Leu Glu 1820 1825 1830 Asp Glu Leu Asn Arg Ala Lys Ser Thr Leu Glu Ala Glu Thr Arg 1835 1840 1845 Val Lys Gln Arg Leu Glu Cys Glu Lys Gln Gln Ile Gln Asn Asp 1850 1855 1860 Leu Asn Gln Trp Lys Thr Gln Tyr Ser Arg Lys Glu Glu Ala Ile 1865 1870 1875 Arg Lys Ile Glu Ser Glu Arg Glu Lys Ser Glu Arg Glu Lys Asn 1880 1885 1890 Ser Leu Arg Ser Glu Ile Glu Arg Leu Gln Ala Glu Ile Lys Arg 1895 1900 1905 Ile Glu Glu Arg Cys Arg Arg Lys Leu Glu Asp Ser Thr Arg Glu 1910 1915

1920 Thr Gln Ser Gln Leu Glu Thr Glu Arg Ser Arg Tyr Gln Arg Glu 1925 1930 1935 Ile Asp Lys Leu Arg Gln Arg Pro Tyr Gly Ser His Arg Glu Thr 1940 1945 1950 Gln Thr Glu Cys Glu Trp Thr Val Asp Thr Ser Lys Leu Val Phe 1955 1960 1965 Asp Gly Leu Arg Lys Lys Val Thr Ala Met Gln Leu Tyr Glu Cys 1970 1975 1980 Gln Leu Ile Asp Lys Thr Thr Leu Asp Lys Leu Leu Lys Gly Lys 1985 1990 1995 Lys Ser Val Glu Glu Val Ala Ser Glu Ile Gln Pro Phe Leu Arg 2000 2005 2010 Gly Ala Gly Ser Ile Ala Gly Ala Ser Ala Ser Pro Lys Glu Lys 2015 2020 2025 Tyr Ser Leu Val Glu Ala Lys Arg Lys Lys Leu Ile Ser Pro Glu 2030 2035 2040 Ser Thr Val Met Leu Leu Glu Ala Gln Ala Ala Thr Gly Gly Ile 2045 2050 2055 Ile Asp Pro His Arg Asn Glu Lys Leu Thr Val Asp Ser Ala Ile 2060 2065 2070 Ala Arg Asp Leu Ile Asp Phe Asp Asp Arg Gln Gln Ile Tyr Ala 2075 2080 2085 Ala Glu Lys Ala Ile Thr Gly Phe Asp Asp Pro Phe Ser Gly Lys 2090 2095 2100 Thr Val Ser Val Ser Glu Ala Ile Lys Lys Asn Leu Ile Asp Arg 2105 2110 2115 Glu Thr Gly Met Arg Leu Leu Glu Ala Gln Ile Ala Ser Gly Gly 2120 2125 2130 Val Val Asp Pro Val Asn Ser Val Phe Leu Pro Lys Asp Val Ala 2135 2140 2145 Leu Ala Arg Gly Leu Ile Asp Arg Asp Leu Tyr Arg Ser Leu Asn 2150 2155 2160 Asp Pro Arg Asp Ser Gln Lys Asn Phe Val Asp Pro Val Thr Lys 2165 2170 2175 Lys Lys Val Ser Tyr Val Gln Leu Lys Glu Arg Cys Arg Ile Glu 2180 2185 2190 Pro His Thr Gly Leu Leu Leu Leu Ser Val Gln Lys Arg Ser Met 2195 2200 2205 Ser Phe Gln Gly Ile Arg Gln Pro Val Thr Val Thr Glu Leu Val 2210 2215 2220 Asp Ser Gly Ile Leu Arg Pro Ser Thr Val Asn Glu Leu Glu Ser 2225 2230 2235 Gly Gln Ile Ser Tyr Asp Glu Val Gly Glu Arg Ile Lys Asp Phe 2240 2245 2250 Leu Gln Gly Ser Ser Cys Ile Ala Gly Ile Tyr Asn Glu Thr Thr 2255 2260 2265 Lys Gln Lys Leu Gly Ile Tyr Glu Ala Met Lys Ile Gly Leu Val 2270 2275 2280 Arg Pro Gly Thr Ala Leu Glu Leu Leu Glu Ala Gln Ala Ala Thr 2285 2290 2295 Gly Phe Ile Val Asp Pro Val Ser Asn Leu Arg Leu Pro Val Glu 2300 2305 2310 Glu Ala Tyr Lys Arg Gly Leu Val Gly Ile Glu Phe Lys Glu Lys 2315 2320 2325 Leu Leu Ser Ala Glu Arg Ala Val Thr Gly Tyr Asn Asp Pro Glu 2330 2335 2340 Thr Gly Asn Ile Ile Ser Leu Phe Gln Ala Met Asn Lys Glu Leu 2345 2350 2355 Ile Glu Lys Gly His Gly Ile Arg Leu Leu Glu Ala Gln Ile Ala 2360 2365 2370 Thr Gly Gly Ile Ile Asp Pro Lys Glu Ser His Arg Leu Pro Val 2375 2380 2385 Asp Ile Ala Tyr Lys Arg Gly Tyr Phe Asn Glu Glu Leu Ser Glu 2390 2395 2400 Ile Leu Ser Asp Pro Ser Asp Asp Thr Lys Gly Phe Phe Asp Pro 2405 2410 2415 Asn Thr Glu Glu Asn Leu Thr Tyr Leu Gln Leu Lys Glu Arg Cys 2420 2425 2430 Ile Lys Asp Glu Glu Thr Gly Leu Cys Leu Leu Pro Leu Lys Glu 2435 2440 2445 Lys Lys Lys Gln Val Gln Thr Ser Gln Lys Asn Thr Leu Arg Lys 2450 2455 2460 Arg Arg Val Val Ile Val Asp Pro Glu Thr Asn Lys Glu Met Ser 2465 2470 2475 Val Gln Glu Ala Tyr Lys Lys Gly Leu Ile Asp Tyr Glu Thr Phe 2480 2485 2490 Lys Glu Leu Cys Glu Gln Glu Cys Glu Trp Glu Glu Ile Thr Ile 2495 2500 2505 Thr Gly Ser Asp Gly Ser Thr Arg Val Val Leu Val Asp Arg Lys 2510 2515 2520 Thr Gly Ser Gln Tyr Asp Ile Gln Asp Ala Ile Asp Lys Gly Leu 2525 2530 2535 Val Asp Arg Lys Phe Phe Asp Gln Tyr Arg Ser Gly Ser Leu Ser 2540 2545 2550 Leu Thr Gln Phe Ala Asp Met Ile Ser Leu Lys Asn Gly Val Gly 2555 2560 2565 Thr Ser Ser Ser Met Gly Ser Gly Val Ser Asp Asp Val Phe Ser 2570 2575 2580 Ser Ser Arg His Glu Ser Val Ser Lys Ile Ser Thr Ile Ser Ser 2585 2590 2595 Val Arg Asn Leu Thr Ile Arg Ser Ser Ser Phe Ser Asp Thr Leu 2600 2605 2610 Glu Glu Ser Ser Pro Ile Ala Ala Ile Phe Asp Thr Glu Asn Leu 2615 2620 2625 Glu Lys Ile Ser Ile Thr Glu Gly Ile Glu Arg Gly Ile Val Asp 2630 2635 2640 Ser Ile Thr Gly Gln Arg Leu Leu Glu Ala Gln Ala Cys Thr Gly 2645 2650 2655 Gly Ile Ile His Pro Thr Thr Gly Gln Lys Leu Ser Leu Gln Asp 2660 2665 2670 Ala Val Ser Gln Gly Val Ile Asp Gln Asp Met Ala Thr Arg Leu 2675 2680 2685 Lys Pro Ala Gln Lys Ala Phe Ile Gly Phe Glu Gly Val Lys Gly 2690 2695 2700 Lys Lys Lys Met Ser Ala Ala Glu Ala Val Lys Glu Lys Trp Leu 2705 2710 2715 Pro Tyr Glu Ala Gly Gln Arg Phe Leu Glu Phe Gln Tyr Leu Thr 2720 2725 2730 Gly Gly Leu Val Asp Pro Glu Val His Gly Arg Ile Ser Thr Glu 2735 2740 2745 Glu Ala Ile Arg Lys Gly Phe Ile Asp Gly Arg Ala Ala Gln Arg 2750 2755 2760 Leu Gln Asp Thr Ser Ser Tyr Ala Lys Ile Leu Thr Cys Pro Lys 2765 2770 2775 Thr Lys Leu Lys Ile Ser Tyr Lys Asp Ala Ile Asn Arg Ser Met 2780 2785 2790 Val Glu Asp Ile Thr Gly Leu Arg Leu Leu Glu Ala Ala Ser Val 2795 2800 2805 Ser Ser Lys Gly Leu Pro Ser Pro Tyr Asn Met Ser Ser Ala Pro 2810 2815 2820 Gly Ser Arg Ser Gly Ser Arg Ser Gly Ser Arg Ser Gly Ser Arg 2825 2830 2835 Ser Gly Ser Arg Ser Gly Ser Arg Arg Gly Ser Phe Asp Ala Thr 2840 2845 2850 Gly Asn Ser Ser Tyr Ser Tyr Ser Tyr Ser Phe Ser Ser Ser Ser 2855 2860 2865 Ile Gly His 2870 80199PRTHomo sapiens 80Met Ser Ser Gly Asn Ala Lys Ile Gly His Pro Ala Pro Asn Phe Lys 1 5 10 15 Ala Thr Ala Val Met Pro Asp Gly Gln Phe Lys Asp Ile Ser Leu Ser 20 25 30 Asp Tyr Lys Gly Lys Tyr Val Val Phe Phe Phe Tyr Pro Leu Asp Phe 35 40 45 Thr Phe Val Cys Pro Thr Glu Ile Ile Ala Phe Ser Asp Arg Ala Glu 50 55 60 Glu Phe Lys Lys Leu Asn Cys Gln Val Ile Gly Ala Ser Val Asp Ser 65 70 75 80 His Phe Cys His Leu Ala Trp Val Asn Thr Pro Lys Lys Gln Gly Gly 85 90 95 Leu Gly Pro Met Asn Ile Pro Leu Val Ser Asp Pro Lys Arg Thr Ile 100 105 110 Ala Gln Asp Tyr Gly Val Leu Lys Ala Asp Glu Gly Ile Ser Phe Arg 115 120 125 Gly Leu Phe Ile Ile Asp Asp Lys Gly Ile Leu Arg Gln Ile Thr Val 130 135 140 Asn Asp Leu Pro Val Gly Arg Ser Val Asp Glu Thr Leu Arg Leu Val 145 150 155 160 Gln Ala Phe Gln Phe Thr Asp Lys His Gly Glu Val Cys Pro Ala Gly 165 170 175 Trp Lys Pro Gly Ser Asp Thr Ile Lys Pro Asp Val Gln Lys Ser Lys 180 185 190 Glu Tyr Phe Ser Lys Gln Lys 195 81508PRTHomo sapiens 81Met Leu Arg Arg Ala Leu Leu Cys Leu Ala Val Ala Ala Leu Val Arg 1 5 10 15 Ala Asp Ala Pro Glu Glu Glu Asp His Val Leu Val Leu Arg Lys Ser 20 25 30 Asn Phe Ala Glu Ala Leu Ala Ala His Lys Tyr Leu Leu Val Glu Phe 35 40 45 Tyr Ala Pro Trp Cys Gly His Cys Lys Ala Leu Ala Pro Glu Tyr Ala 50 55 60 Lys Ala Ala Gly Lys Leu Lys Ala Glu Gly Ser Glu Ile Arg Leu Ala 65 70 75 80 Lys Val Asp Ala Thr Glu Glu Ser Asp Leu Ala Gln Gln Tyr Gly Val 85 90 95 Arg Gly Tyr Pro Thr Ile Lys Phe Phe Arg Asn Gly Asp Thr Ala Ser 100 105 110 Pro Lys Glu Tyr Thr Ala Gly Arg Glu Ala Asp Asp Ile Val Asn Trp 115 120 125 Leu Lys Lys Arg Thr Gly Pro Ala Ala Thr Thr Leu Pro Asp Gly Ala 130 135 140 Ala Ala Glu Ser Leu Val Glu Ser Ser Glu Val Ala Val Ile Gly Phe 145 150 155 160 Phe Lys Asp Val Glu Ser Asp Ser Ala Lys Gln Phe Leu Gln Ala Ala 165 170 175 Glu Ala Ile Asp Asp Ile Pro Phe Gly Ile Thr Ser Asn Ser Asp Val 180 185 190 Phe Ser Lys Tyr Gln Leu Asp Lys Asp Gly Val Val Leu Phe Lys Lys 195 200 205 Phe Asp Glu Gly Arg Asn Asn Phe Glu Gly Glu Val Thr Lys Glu Asn 210 215 220 Leu Leu Asp Phe Ile Lys His Asn Gln Leu Pro Leu Val Ile Glu Phe 225 230 235 240 Thr Glu Gln Thr Ala Pro Lys Ile Phe Gly Gly Glu Ile Lys Thr His 245 250 255 Ile Leu Leu Phe Leu Pro Lys Ser Val Ser Asp Tyr Asp Gly Lys Leu 260 265 270 Ser Asn Phe Lys Thr Ala Ala Glu Ser Phe Lys Gly Lys Ile Leu Phe 275 280 285 Ile Phe Ile Asp Ser Asp His Thr Asp Asn Gln Arg Ile Leu Glu Phe 290 295 300 Phe Gly Leu Lys Lys Glu Glu Cys Pro Ala Val Arg Leu Ile Thr Leu 305 310 315 320 Glu Glu Glu Met Thr Lys Tyr Lys Pro Glu Ser Glu Glu Leu Thr Ala 325 330 335 Glu Arg Ile Thr Glu Phe Cys His Arg Phe Leu Glu Gly Lys Ile Lys 340 345 350 Pro His Leu Met Ser Gln Glu Leu Pro Glu Asp Trp Asp Lys Gln Pro 355 360 365 Val Lys Val Leu Val Gly Lys Asn Phe Glu Asp Val Ala Phe Asp Glu 370 375 380 Lys Lys Asn Val Phe Val Glu Phe Tyr Ala Pro Trp Cys Gly His Cys 385 390 395 400 Lys Gln Leu Ala Pro Ile Trp Asp Lys Leu Gly Glu Thr Tyr Lys Asp 405 410 415 His Glu Asn Ile Val Ile Ala Lys Met Asp Ser Thr Ala Asn Glu Val 420 425 430 Glu Ala Val Lys Val His Ser Phe Pro Thr Leu Lys Phe Phe Pro Ala 435 440 445 Ser Ala Asp Arg Thr Val Ile Asp Tyr Asn Gly Glu Arg Thr Leu Asp 450 455 460 Gly Phe Lys Lys Phe Leu Glu Ser Gly Gly Gln Asp Gly Ala Gly Asp 465 470 475 480 Asp Asp Asp Leu Glu Asp Leu Glu Glu Ala Glu Glu Pro Asp Met Glu 485 490 495 Glu Asp Asp Asp Gln Lys Ala Val Lys Asp Glu Leu 500 505 82219PRTHomo sapiens 82Met Ser Glu Thr Ala Pro Ala Ala Pro Ala Ala Pro Ala Pro Ala Glu 1 5 10 15 Lys Thr Pro Val Lys Lys Lys Ala Arg Lys Ser Ala Gly Ala Ala Lys 20 25 30 Arg Lys Ala Ser Gly Pro Pro Val Ser Glu Leu Ile Thr Lys Ala Val 35 40 45 Ala Ala Ser Lys Glu Arg Ser Gly Val Ser Leu Ala Ala Leu Lys Lys 50 55 60 Ala Leu Ala Ala Ala Gly Tyr Asp Val Glu Lys Asn Asn Ser Arg Ile 65 70 75 80 Lys Leu Gly Leu Lys Ser Leu Val Ser Lys Gly Thr Leu Val Gln Thr 85 90 95 Lys Gly Thr Gly Ala Ser Gly Ser Phe Lys Leu Asn Lys Lys Ala Ala 100 105 110 Ser Gly Glu Ala Lys Pro Lys Ala Lys Lys Ala Gly Ala Ala Lys Ala 115 120 125 Lys Lys Pro Ala Gly Ala Ala Lys Lys Pro Lys Lys Ala Thr Gly Ala 130 135 140 Ala Thr Pro Lys Lys Ser Ala Lys Lys Thr Pro Lys Lys Ala Lys Lys 145 150 155 160 Pro Ala Ala Ala Ala Gly Ala Lys Lys Ala Lys Ser Pro Lys Lys Ala 165 170 175 Lys Ala Ala Lys Pro Lys Lys Ala Pro Lys Ser Pro Ala Lys Ala Lys 180 185 190 Ala Val Lys Pro Lys Ala Ala Lys Pro Lys Thr Ala Lys Pro Lys Ala 195 200 205 Ala Lys Pro Lys Lys Ala Ala Ala Lys Lys Lys 210 215 83165PRTHomo sapiens 83Met Pro Pro Lys Phe Asp Pro Asn Glu Ile Lys Val Val Tyr Leu Arg 1 5 10 15 Cys Thr Gly Gly Glu Val Gly Ala Thr Ser Ala Leu Ala Pro Lys Ile 20 25 30 Gly Pro Leu Gly Leu Ser Pro Lys Lys Val Gly Asp Asp Ile Ala Lys 35 40 45 Ala Thr Gly Asp Trp Lys Gly Leu Arg Ile Thr Val Lys Leu Thr Ile 50 55 60 Gln Asn Arg Gln Ala Gln Ile Glu Val Val Pro Ser Ala Ser Ala Leu 65 70 75 80 Ile Ile Lys Ala Leu Lys Glu Pro Pro Arg Asp Arg Lys Lys Gln Lys 85 90 95 Asn Ile Lys His Ser Gly Asn Ile Thr Phe Asp Glu Ile Val Asn Ile 100 105 110 Ala Arg Gln Met Arg His Arg Ser Leu Ala Arg Glu Leu Ser Gly Thr 115 120 125 Ile Lys Glu Ile Leu Gly Thr Ala Gln Ser Val Gly Cys Asn Val Asp 130 135 140 Gly Arg His Pro His Asp Ile Ile Asp Asp Ile Asn Ser Gly Ala Val 145 150 155 160 Glu Cys Pro Ala Ser 165 84448PRTHomo sapiens 84Met Arg Glu Cys Ile Ser Val His Val Gly Gln Ala Gly Val Gln Met 1 5 10 15 Gly Asn Ala Cys Trp Glu Leu Tyr Cys Leu Glu His Gly Ile Gln Pro 20 25 30 Asp Gly Gln Met Pro Ser Asp Lys Thr Ile Gly Gly Gly Asp Asp Ser 35 40 45 Phe Thr Thr Phe Phe Cys Glu Thr Gly Ala Gly Lys His Val Pro Arg 50 55 60 Ala Val Phe Val Asp Leu Glu Pro Thr Val Ile Asp Glu Ile Arg Asn 65 70 75 80 Gly Pro Tyr Arg Gln Leu Phe His Pro Glu Gln Leu Ile Thr Gly Lys 85 90 95 Glu Asp Ala Ala Asn Asn Tyr Ala Arg Gly His Tyr Thr Ile Gly Lys 100 105 110 Glu Ile Ile Asp Pro Val Leu Asp Arg Ile Arg Lys Leu Ser Asp Gln 115 120 125 Cys Thr Gly Leu Gln Gly Phe Leu Val Phe His Ser Phe Gly Gly Gly 130 135 140 Thr Gly Ser Gly Phe Thr Ser Leu Leu Met Glu Arg Leu Ser Val Asp 145 150 155 160 Tyr Gly Lys Lys Ser Lys Leu Glu Phe Ser Ile Tyr Pro Ala Pro Gln 165 170 175 Val Ser Thr Ala Val Val Glu Pro Tyr Asn Ser Ile Leu Thr Thr His 180 185 190 Thr Thr Leu Glu His Ser Asp Cys Ala Phe Met Val Asp Asn Glu Ala 195

200 205 Ile Tyr Asp Ile Cys Arg Arg Asn Leu Asp Ile Glu Arg Pro Thr Tyr 210 215 220 Thr Asn Leu Asn Arg Leu Ile Ser Gln Ile Val Ser Ser Ile Thr Ala 225 230 235 240 Ser Leu Arg Phe Asp Gly Ala Leu Asn Val Asp Leu Thr Glu Phe Gln 245 250 255 Thr Asn Leu Val Pro Tyr Pro Arg Ile His Phe Pro Leu Ala Thr Tyr 260 265 270 Ala Pro Val Ile Ser Ala Glu Lys Ala Tyr His Glu Gln Leu Ser Val 275 280 285 Ala Glu Ile Thr Asn Ala Cys Phe Glu Pro Ala Asn Gln Met Val Lys 290 295 300 Cys Asp Pro Arg His Gly Lys Tyr Met Ala Cys Cys Leu Leu Tyr Arg 305 310 315 320 Gly Asp Val Val Pro Lys Asp Val Asn Ala Ala Ile Ala Ala Ile Lys 325 330 335 Thr Lys Arg Ser Ile Gln Phe Val Asp Trp Cys Pro Thr Gly Phe Lys 340 345 350 Val Gly Ile Asn Tyr Gln Pro Pro Thr Val Val Pro Gly Gly Asp Leu 355 360 365 Ala Lys Val Gln Arg Ala Val Cys Met Leu Ser Asn Thr Thr Ala Ile 370 375 380 Ala Glu Ala Trp Ala Arg Leu Asp His Lys Phe Asp Leu Met Tyr Ala 385 390 395 400 Lys Arg Ala Phe Val His Trp Tyr Val Gly Glu Gly Met Glu Glu Gly 405 410 415 Glu Phe Ser Glu Ala Arg Glu Asp Met Ala Ala Leu Glu Lys Asp Tyr 420 425 430 Glu Glu Val Gly Ile Asp Ser Tyr Glu Asp Glu Asp Glu Gly Glu Glu 435 440 445 85450PRTHomo sapiens 85Met Arg Glu Ile Val His Ile Gln Ala Gly Gln Cys Gly Asn Gln Ile 1 5 10 15 Gly Ala Lys Phe Trp Glu Val Ile Ser Asp Glu His Gly Ile Asp Pro 20 25 30 Ser Gly Asn Tyr Val Gly Asp Ser Asp Leu Gln Leu Glu Arg Ile Ser 35 40 45 Val Tyr Tyr Asn Glu Ala Ser Ser His Lys Tyr Val Pro Arg Ala Ile 50 55 60 Leu Val Asp Leu Glu Pro Gly Thr Met Asp Ser Val Arg Ser Gly Ala 65 70 75 80 Phe Gly His Leu Phe Arg Pro Asp Asn Phe Ile Phe Gly Gln Ser Gly 85 90 95 Ala Gly Asn Asn Trp Ala Lys Gly His Tyr Thr Glu Gly Ala Glu Leu 100 105 110 Val Asp Ser Val Leu Asp Val Val Arg Lys Glu Cys Glu Asn Cys Asp 115 120 125 Cys Leu Gln Gly Phe Gln Leu Thr His Ser Leu Gly Gly Gly Thr Gly 130 135 140 Ser Gly Met Gly Thr Leu Leu Ile Ser Lys Val Arg Glu Glu Tyr Pro 145 150 155 160 Asp Arg Ile Met Asn Thr Phe Ser Val Val Pro Ser Pro Lys Val Ser 165 170 175 Asp Thr Val Val Glu Pro Tyr Asn Ala Thr Leu Ser Ile His Gln Leu 180 185 190 Val Glu Asn Thr Asp Glu Thr Tyr Cys Ile Asp Asn Glu Ala Leu Tyr 195 200 205 Asp Ile Cys Phe Arg Thr Leu Lys Leu Ala Thr Pro Thr Tyr Gly Asp 210 215 220 Leu Asn His Leu Val Ser Ala Thr Met Ser Gly Val Thr Thr Ser Leu 225 230 235 240 Arg Phe Pro Gly Gln Leu Asn Ala Asp Leu Arg Lys Leu Ala Val Asn 245 250 255 Met Val Pro Phe Pro Arg Leu His Phe Phe Met Pro Gly Phe Ala Pro 260 265 270 Leu Thr Ala Arg Gly Ser Gln Gln Tyr Arg Ala Leu Thr Val Pro Glu 275 280 285 Leu Thr Gln Gln Met Phe Asp Ala Lys Asn Met Met Ala Ala Cys Asp 290 295 300 Pro Arg His Gly Arg Tyr Leu Thr Val Ala Thr Val Phe Arg Gly Arg 305 310 315 320 Met Ser Met Lys Glu Val Asp Glu Gln Met Leu Ala Ile Gln Ser Lys 325 330 335 Asn Ser Ser Tyr Phe Val Glu Trp Ile Pro Asn Asn Val Lys Val Ala 340 345 350 Val Cys Asp Ile Pro Pro Arg Gly Leu Lys Met Ser Ser Thr Phe Ile 355 360 365 Gly Asn Ser Thr Ala Ile Gln Glu Leu Phe Lys Arg Ile Ser Glu Gln 370 375 380 Phe Thr Ala Met Phe Arg Arg Lys Ala Phe Leu His Trp Tyr Thr Gly 385 390 395 400 Glu Gly Met Asp Glu Met Glu Phe Thr Glu Ala Glu Ser Asn Met Asn 405 410 415 Asp Leu Val Ser Glu Tyr Gln Gln Tyr Gln Asp Ala Thr Ala Glu Glu 420 425 430 Glu Gly Glu Met Tyr Glu Asp Asp Glu Glu Glu Ser Glu Ala Gln Gly 435 440 445 Pro Lys 450 86247PRTHomo sapiens 86Met Val Asp Arg Glu Gln Leu Val Gln Lys Ala Arg Leu Ala Glu Gln 1 5 10 15 Ala Glu Arg Tyr Asp Asp Met Ala Ala Ala Met Lys Asn Val Thr Glu 20 25 30 Leu Asn Glu Pro Leu Ser Asn Glu Glu Arg Asn Leu Leu Ser Val Ala 35 40 45 Tyr Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Ile Ser 50 55 60 Ser Ile Glu Gln Lys Thr Ser Ala Asp Gly Asn Glu Lys Lys Ile Glu 65 70 75 80 Met Val Arg Ala Tyr Arg Glu Lys Ile Glu Lys Glu Leu Glu Ala Val 85 90 95 Cys Gln Asp Val Leu Ser Leu Leu Asp Asn Tyr Leu Ile Lys Asn Cys 100 105 110 Ser Glu Thr Gln Tyr Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly 115 120 125 Asp Tyr Tyr Arg Tyr Leu Ala Glu Val Ala Thr Gly Glu Lys Arg Ala 130 135 140 Thr Val Val Glu Ser Ser Glu Lys Ala Tyr Ser Glu Ala His Glu Ile 145 150 155 160 Ser Lys Glu His Met Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala 165 170 175 Leu Asn Tyr Ser Val Phe Tyr Tyr Glu Ile Gln Asn Ala Pro Glu Gln 180 185 190 Ala Cys His Leu Ala Lys Thr Ala Phe Asp Asp Ala Ile Ala Glu Leu 195 200 205 Asp Thr Leu Asn Glu Asp Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln 210 215 220 Leu Leu Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Gln Gln Asp Asp 225 230 235 240 Asp Gly Gly Glu Gly Asn Asn 245 87466PRTHomo sapiens 87Met Ser Thr Arg Ser Val Ser Ser Ser Ser Tyr Arg Arg Met Phe Gly 1 5 10 15 Gly Pro Gly Thr Ala Ser Arg Pro Ser Ser Ser Arg Ser Tyr Val Thr 20 25 30 Thr Ser Thr Arg Thr Tyr Ser Leu Gly Ser Ala Leu Arg Pro Ser Thr 35 40 45 Ser Arg Ser Leu Tyr Ala Ser Ser Pro Gly Gly Val Tyr Ala Thr Arg 50 55 60 Ser Ser Ala Val Arg Leu Arg Ser Ser Val Pro Gly Val Arg Leu Leu 65 70 75 80 Gln Asp Ser Val Asp Phe Ser Leu Ala Asp Ala Ile Asn Thr Glu Phe 85 90 95 Lys Asn Thr Arg Thr Asn Glu Lys Val Glu Leu Gln Glu Leu Asn Asp 100 105 110 Arg Phe Ala Asn Tyr Ile Asp Lys Val Arg Phe Leu Glu Gln Gln Asn 115 120 125 Lys Ile Leu Leu Ala Glu Leu Glu Gln Leu Lys Gly Gln Gly Lys Ser 130 135 140 Arg Leu Gly Asp Leu Tyr Glu Glu Glu Met Arg Glu Leu Arg Arg Gln 145 150 155 160 Val Asp Gln Leu Thr Asn Asp Lys Ala Arg Val Glu Val Glu Arg Asp 165 170 175 Asn Leu Ala Glu Asp Ile Met Arg Leu Arg Glu Lys Leu Gln Glu Glu 180 185 190 Met Leu Gln Arg Glu Glu Ala Glu Asn Thr Leu Gln Ser Phe Arg Gln 195 200 205 Asp Val Asp Asn Ala Ser Leu Ala Arg Leu Asp Leu Glu Arg Lys Val 210 215 220 Glu Ser Leu Gln Glu Glu Ile Ala Phe Leu Lys Lys Leu His Glu Glu 225 230 235 240 Glu Ile Gln Glu Leu Gln Ala Gln Ile Gln Glu Gln His Val Gln Ile 245 250 255 Asp Val Asp Val Ser Lys Pro Asp Leu Thr Ala Ala Leu Arg Asp Val 260 265 270 Arg Gln Gln Tyr Glu Ser Val Ala Ala Lys Asn Leu Gln Glu Ala Glu 275 280 285 Glu Trp Tyr Lys Ser Lys Phe Ala Asp Leu Ser Glu Ala Ala Asn Arg 290 295 300 Asn Asn Asp Ala Leu Arg Gln Ala Lys Gln Glu Ser Thr Glu Tyr Arg 305 310 315 320 Arg Gln Val Gln Ser Leu Thr Cys Glu Val Asp Ala Leu Lys Gly Thr 325 330 335 Asn Glu Ser Leu Glu Arg Gln Met Arg Glu Met Glu Glu Asn Phe Ala 340 345 350 Val Glu Ala Ala Asn Tyr Gln Asp Thr Ile Gly Arg Leu Gln Asp Glu 355 360 365 Ile Gln Asn Met Lys Glu Glu Met Ala Arg His Leu Arg Glu Tyr Gln 370 375 380 Asp Leu Leu Asn Val Lys Met Ala Leu Asp Ile Glu Ile Ala Thr Tyr 385 390 395 400 Arg Lys Leu Leu Glu Gly Glu Glu Ser Arg Ile Ser Leu Pro Leu Pro 405 410 415 Asn Phe Ser Ser Leu Asn Leu Arg Glu Thr Asn Leu Asp Ser Leu Pro 420 425 430 Leu Val Asp Thr His Ser Lys Arg Thr Leu Leu Ile Lys Thr Val Glu 435 440 445 Thr Arg Asp Gly Gln Val Ile Asn Glu Thr Ser Gln His His Asp Asp 450 455 460 Leu Glu 465 882647PRTHomo sapiens 88Met Ser Ser Ser His Ser Arg Ala Gly Gln Ser Ala Ala Gly Ala Ala 1 5 10 15 Pro Gly Gly Gly Val Asp Thr Arg Asp Ala Glu Met Pro Ala Thr Glu 20 25 30 Lys Asp Leu Ala Glu Asp Ala Pro Trp Lys Lys Ile Gln Gln Asn Thr 35 40 45 Phe Thr Arg Trp Cys Asn Glu His Leu Lys Cys Val Ser Lys Arg Ile 50 55 60 Ala Asn Leu Gln Thr Asp Leu Ser Asp Gly Leu Arg Leu Ile Ala Leu 65 70 75 80 Leu Glu Val Leu Ser Gln Lys Lys Met His Arg Lys His Asn Gln Arg 85 90 95 Pro Thr Phe Arg Gln Met Gln Leu Glu Asn Val Ser Val Ala Leu Glu 100 105 110 Phe Leu Asp Arg Glu Ser Ile Lys Leu Val Ser Ile Asp Ser Lys Ala 115 120 125 Ile Val Asp Gly Asn Leu Lys Leu Ile Leu Gly Leu Ile Trp Thr Leu 130 135 140 Ile Leu His Tyr Ser Ile Ser Met Pro Met Trp Asp Glu Glu Glu Asp 145 150 155 160 Glu Glu Ala Lys Lys Gln Thr Pro Lys Gln Arg Leu Leu Gly Trp Ile 165 170 175 Gln Asn Lys Leu Pro Gln Leu Pro Ile Thr Asn Phe Ser Arg Asp Trp 180 185 190 Gln Ser Gly Arg Ala Leu Gly Ala Leu Val Asp Ser Cys Ala Pro Gly 195 200 205 Leu Cys Pro Asp Trp Asp Ser Trp Asp Ala Ser Lys Pro Val Thr Asn 210 215 220 Ala Arg Glu Ala Met Gln Gln Ala Asp Asp Trp Leu Gly Ile Pro Gln 225 230 235 240 Val Ile Thr Pro Glu Glu Ile Val Asp Pro Asn Val Asp Glu His Ser 245 250 255 Val Met Thr Tyr Leu Ser Gln Phe Pro Lys Ala Lys Leu Lys Pro Gly 260 265 270 Ala Pro Leu Arg Pro Lys Leu Asn Pro Lys Lys Ala Arg Ala Tyr Gly 275 280 285 Pro Gly Ile Glu Pro Thr Gly Asn Met Val Lys Lys Arg Ala Glu Phe 290 295 300 Thr Val Glu Thr Arg Ser Ala Gly Gln Gly Glu Val Leu Val Tyr Val 305 310 315 320 Glu Asp Pro Ala Gly His Gln Glu Glu Ala Lys Val Thr Ala Asn Asn 325 330 335 Asp Lys Asn Arg Thr Phe Ser Val Trp Tyr Val Pro Glu Val Thr Gly 340 345 350 Thr His Lys Val Thr Val Leu Phe Ala Gly Gln His Ile Ala Lys Ser 355 360 365 Pro Phe Glu Val Tyr Val Asp Lys Ser Gln Gly Asp Ala Ser Lys Val 370 375 380 Thr Ala Gln Gly Pro Gly Leu Glu Pro Ser Gly Asn Ile Ala Asn Lys 385 390 395 400 Thr Thr Tyr Phe Glu Ile Phe Thr Ala Gly Ala Gly Thr Gly Glu Val 405 410 415 Glu Val Val Ile Gln Asp Pro Met Gly Gln Lys Gly Thr Val Glu Pro 420 425 430 Gln Leu Glu Ala Arg Gly Asp Ser Thr Tyr Arg Cys Ser Tyr Gln Pro 435 440 445 Thr Met Glu Gly Val His Thr Val His Val Thr Phe Ala Gly Val Pro 450 455 460 Ile Pro Arg Ser Pro Tyr Thr Val Thr Val Gly Gln Ala Cys Asn Pro 465 470 475 480 Ser Ala Cys Arg Ala Val Gly Arg Gly Leu Gln Pro Lys Gly Val Arg 485 490 495 Val Lys Glu Thr Ala Asp Phe Lys Val Tyr Thr Lys Gly Ala Gly Ser 500 505 510 Gly Glu Leu Lys Val Thr Val Lys Gly Pro Lys Gly Glu Glu Arg Val 515 520 525 Lys Gln Lys Asp Leu Gly Asp Gly Val Tyr Gly Phe Glu Tyr Tyr Pro 530 535 540 Met Val Pro Gly Thr Tyr Ile Val Thr Ile Thr Trp Gly Gly Gln Asn 545 550 555 560 Ile Gly Arg Ser Pro Phe Glu Val Lys Val Gly Thr Glu Cys Gly Asn 565 570 575 Gln Lys Val Arg Ala Trp Gly Pro Gly Leu Glu Gly Gly Val Val Gly 580 585 590 Lys Ser Ala Asp Phe Val Val Glu Ala Ile Gly Asp Asp Val Gly Thr 595 600 605 Leu Gly Phe Ser Val Glu Gly Pro Ser Gln Ala Lys Ile Glu Cys Asp 610 615 620 Asp Lys Gly Asp Gly Ser Cys Asp Val Arg Tyr Trp Pro Gln Glu Ala 625 630 635 640 Gly Glu Tyr Ala Val His Val Leu Cys Asn Ser Glu Asp Ile Arg Leu 645 650 655 Ser Pro Phe Met Ala Asp Ile Arg Asp Ala Pro Gln Asp Phe His Pro 660 665 670 Asp Arg Val Lys Ala Arg Gly Pro Gly Leu Glu Lys Thr Gly Val Ala 675 680 685 Val Asn Lys Pro Ala Glu Phe Thr Val Asp Ala Lys His Gly Gly Lys 690 695 700 Ala Pro Leu Arg Val Gln Val Gln Asp Asn Glu Gly Cys Pro Val Glu 705 710 715 720 Ala Leu Val Lys Asp Asn Gly Asn Gly Thr Tyr Ser Cys Ser Tyr Val 725 730 735 Pro Arg Lys Pro Val Lys His Thr Ala Met Val Ser Trp Gly Gly Val 740 745 750 Ser Ile Pro Asn Ser Pro Phe Arg Val Asn Val Gly Ala Gly Ser His 755 760 765 Pro Asn Lys Val Lys Val Tyr Gly Pro Gly Val Ala Lys Thr Gly Leu 770 775 780 Lys Ala His Glu Pro Thr Tyr Phe Thr Val Asp Cys Ala Glu Ala Gly 785 790 795 800 Gln Gly Asp Val Ser Ile Gly Ile Lys Cys Ala Pro Gly Val Val Gly 805 810 815 Pro Ala Glu Ala Asp Ile Asp Phe Asp Ile Ile Arg Asn Asp Asn Asp 820 825 830 Thr Phe Thr Val Lys Tyr Thr Pro Arg Gly Ala Gly Ser Tyr Thr Ile 835 840 845 Met Val Leu Phe Ala Asp Gln Ala Thr Pro Thr Ser Pro Ile Arg Val 850 855 860 Lys Val Glu Pro Ser His Asp Ala Ser Lys Val Lys Ala Glu Gly Pro 865 870 875 880 Gly Leu Ser Arg Thr Gly Val Glu Leu Gly Lys Pro

Thr His Phe Thr 885 890 895 Val Asn Ala Lys Ala Ala Gly Lys Gly Lys Leu Asp Val Gln Phe Ser 900 905 910 Gly Leu Thr Lys Gly Asp Ala Val Arg Asp Val Asp Ile Ile Asp His 915 920 925 His Asp Asn Thr Tyr Thr Val Lys Tyr Thr Pro Val Gln Gln Gly Pro 930 935 940 Val Gly Val Asn Val Thr Tyr Gly Gly Asp Pro Ile Pro Lys Ser Pro 945 950 955 960 Phe Ser Val Ala Val Ser Pro Ser Leu Asp Leu Ser Lys Ile Lys Val 965 970 975 Ser Gly Leu Gly Glu Lys Val Asp Val Gly Lys Asp Gln Glu Phe Thr 980 985 990 Val Lys Ser Lys Gly Ala Gly Gly Gln Gly Lys Val Ala Ser Lys Ile 995 1000 1005 Val Gly Pro Ser Gly Ala Ala Val Pro Cys Lys Val Glu Pro Gly 1010 1015 1020 Leu Gly Ala Asp Asn Ser Val Val Arg Phe Leu Pro Arg Glu Glu 1025 1030 1035 Gly Pro Tyr Glu Val Glu Val Thr Tyr Asp Gly Val Pro Val Pro 1040 1045 1050 Gly Ser Pro Phe Pro Leu Glu Ala Val Ala Pro Thr Lys Pro Ser 1055 1060 1065 Lys Val Lys Ala Phe Gly Pro Gly Leu Gln Gly Gly Ser Ala Gly 1070 1075 1080 Ser Pro Ala Arg Phe Thr Ile Asp Thr Lys Gly Ala Gly Thr Gly 1085 1090 1095 Gly Leu Gly Leu Thr Val Glu Gly Pro Cys Glu Ala Gln Leu Glu 1100 1105 1110 Cys Leu Asp Asn Gly Asp Gly Thr Cys Ser Val Ser Tyr Val Pro 1115 1120 1125 Thr Glu Pro Gly Asp Tyr Asn Ile Asn Ile Leu Phe Ala Asp Thr 1130 1135 1140 His Ile Pro Gly Ser Pro Phe Lys Ala His Val Val Pro Cys Phe 1145 1150 1155 Asp Ala Ser Lys Val Lys Cys Ser Gly Pro Gly Leu Glu Arg Ala 1160 1165 1170 Thr Ala Gly Glu Val Gly Gln Phe Gln Val Asp Cys Ser Ser Ala 1175 1180 1185 Gly Ser Ala Glu Leu Thr Ile Glu Ile Cys Ser Glu Ala Gly Leu 1190 1195 1200 Pro Ala Glu Val Tyr Ile Gln Asp His Gly Asp Gly Thr His Thr 1205 1210 1215 Ile Thr Tyr Ile Pro Leu Cys Pro Gly Ala Tyr Thr Val Thr Ile 1220 1225 1230 Lys Tyr Gly Gly Gln Pro Val Pro Asn Phe Pro Ser Lys Leu Gln 1235 1240 1245 Val Glu Pro Ala Val Asp Thr Ser Gly Val Gln Cys Tyr Gly Pro 1250 1255 1260 Gly Ile Glu Gly Gln Gly Val Phe Arg Glu Ala Thr Thr Glu Phe 1265 1270 1275 Ser Val Asp Ala Arg Ala Leu Thr Gln Thr Gly Gly Pro His Val 1280 1285 1290 Lys Ala Arg Val Ala Asn Pro Ser Gly Asn Leu Thr Glu Thr Tyr 1295 1300 1305 Val Gln Asp Arg Gly Asp Gly Met Tyr Lys Val Glu Tyr Thr Pro 1310 1315 1320 Tyr Glu Glu Gly Leu His Ser Val Asp Val Thr Tyr Asp Gly Ser 1325 1330 1335 Pro Val Pro Ser Ser Pro Phe Gln Val Pro Val Thr Glu Gly Cys 1340 1345 1350 Asp Pro Ser Arg Val Arg Val His Gly Pro Gly Ile Gln Ser Gly 1355 1360 1365 Thr Thr Asn Lys Pro Asn Lys Phe Thr Val Glu Thr Arg Gly Ala 1370 1375 1380 Gly Thr Gly Gly Leu Gly Leu Ala Val Glu Gly Pro Ser Glu Ala 1385 1390 1395 Lys Met Ser Cys Met Asp Asn Lys Asp Gly Ser Cys Ser Val Glu 1400 1405 1410 Tyr Ile Pro Tyr Glu Ala Gly Thr Tyr Ser Leu Asn Val Thr Tyr 1415 1420 1425 Gly Gly His Gln Val Pro Gly Ser Pro Phe Lys Val Pro Val His 1430 1435 1440 Asp Val Thr Asp Ala Ser Lys Val Lys Cys Ser Gly Pro Gly Leu 1445 1450 1455 Ser Pro Gly Met Val Arg Ala Asn Leu Pro Gln Ser Phe Gln Val 1460 1465 1470 Asp Thr Ser Lys Ala Gly Val Ala Pro Leu Gln Val Lys Val Gln 1475 1480 1485 Gly Pro Lys Gly Leu Val Glu Pro Val Asp Val Val Asp Asn Ala 1490 1495 1500 Asp Gly Thr Gln Thr Val Asn Tyr Val Pro Ser Arg Glu Gly Pro 1505 1510 1515 Tyr Ser Ile Ser Val Leu Tyr Gly Asp Glu Glu Val Pro Arg Ser 1520 1525 1530 Pro Phe Lys Val Lys Val Leu Pro Thr His Asp Ala Ser Lys Val 1535 1540 1545 Lys Ala Ser Gly Pro Gly Leu Asn Thr Thr Gly Val Pro Ala Ser 1550 1555 1560 Leu Pro Val Glu Phe Thr Ile Asp Ala Lys Asp Ala Gly Glu Gly 1565 1570 1575 Leu Leu Ala Val Gln Ile Thr Asp Pro Glu Gly Lys Pro Lys Lys 1580 1585 1590 Thr His Ile Gln Asp Asn His Asp Gly Thr Tyr Thr Val Ala Tyr 1595 1600 1605 Val Pro Asp Val Thr Gly Arg Tyr Thr Ile Leu Ile Lys Tyr Gly 1610 1615 1620 Gly Asp Glu Ile Pro Phe Ser Pro Tyr Arg Val Arg Ala Val Pro 1625 1630 1635 Thr Gly Asp Ala Ser Lys Cys Thr Val Thr Val Ser Ile Gly Gly 1640 1645 1650 His Gly Leu Gly Ala Gly Ile Gly Pro Thr Ile Gln Ile Gly Glu 1655 1660 1665 Glu Thr Val Ile Thr Val Asp Thr Lys Ala Ala Gly Lys Gly Lys 1670 1675 1680 Val Thr Cys Thr Val Cys Thr Pro Asp Gly Ser Glu Val Asp Val 1685 1690 1695 Asp Val Val Glu Asn Glu Asp Gly Thr Phe Asp Ile Phe Tyr Thr 1700 1705 1710 Ala Pro Gln Pro Gly Lys Tyr Val Ile Cys Val Arg Phe Gly Gly 1715 1720 1725 Glu His Val Pro Asn Ser Pro Phe Gln Val Thr Ala Leu Ala Gly 1730 1735 1740 Asp Gln Pro Ser Val Gln Pro Pro Leu Arg Ser Gln Gln Leu Ala 1745 1750 1755 Pro Gln Tyr Thr Tyr Ala Gln Gly Gly Gln Gln Thr Trp Ala Pro 1760 1765 1770 Glu Arg Pro Leu Val Gly Val Asn Gly Leu Asp Val Thr Ser Leu 1775 1780 1785 Arg Pro Phe Asp Leu Val Ile Pro Phe Thr Ile Lys Lys Gly Glu 1790 1795 1800 Ile Thr Gly Glu Val Arg Met Pro Ser Gly Lys Val Ala Gln Pro 1805 1810 1815 Thr Ile Thr Asp Asn Lys Asp Gly Thr Val Thr Val Arg Tyr Ala 1820 1825 1830 Pro Ser Glu Ala Gly Leu His Glu Met Asp Ile Arg Tyr Asp Asn 1835 1840 1845 Met His Ile Pro Gly Ser Pro Leu Gln Phe Tyr Val Asp Tyr Val 1850 1855 1860 Asn Cys Gly His Val Thr Ala Tyr Gly Pro Gly Leu Thr His Gly 1865 1870 1875 Val Val Asn Lys Pro Ala Thr Phe Thr Val Asn Thr Lys Asp Ala 1880 1885 1890 Gly Glu Gly Gly Leu Ser Leu Ala Ile Glu Gly Pro Ser Lys Ala 1895 1900 1905 Glu Ile Ser Cys Thr Asp Asn Gln Asp Gly Thr Cys Ser Val Ser 1910 1915 1920 Tyr Leu Pro Val Leu Pro Gly Asp Tyr Ser Ile Leu Val Lys Tyr 1925 1930 1935 Asn Glu Gln His Val Pro Gly Ser Pro Phe Thr Ala Arg Val Thr 1940 1945 1950 Gly Asp Asp Ser Met Arg Met Ser His Leu Lys Val Gly Ser Ala 1955 1960 1965 Ala Asp Ile Pro Ile Asn Ile Ser Glu Thr Asp Leu Ser Leu Leu 1970 1975 1980 Thr Ala Thr Val Val Pro Pro Ser Gly Arg Glu Glu Pro Cys Leu 1985 1990 1995 Leu Lys Arg Leu Arg Asn Gly His Val Gly Ile Ser Phe Val Pro 2000 2005 2010 Lys Glu Thr Gly Glu His Leu Val His Val Lys Lys Asn Gly Gln 2015 2020 2025 His Val Ala Ser Ser Pro Ile Pro Val Val Ile Ser Gln Ser Glu 2030 2035 2040 Ile Gly Asp Ala Ser Arg Val Arg Val Ser Gly Gln Gly Leu His 2045 2050 2055 Glu Gly His Thr Phe Glu Pro Ala Glu Phe Ile Ile Asp Thr Arg 2060 2065 2070 Asp Ala Gly Tyr Gly Gly Leu Ser Leu Ser Ile Glu Gly Pro Ser 2075 2080 2085 Lys Val Asp Ile Asn Thr Glu Asp Leu Glu Asp Gly Thr Cys Arg 2090 2095 2100 Val Thr Tyr Cys Pro Thr Glu Pro Gly Asn Tyr Ile Ile Asn Ile 2105 2110 2115 Lys Phe Ala Asp Gln His Val Pro Gly Ser Pro Phe Ser Val Lys 2120 2125 2130 Val Thr Gly Glu Gly Arg Val Lys Glu Ser Ile Thr Arg Arg Arg 2135 2140 2145 Arg Ala Pro Ser Val Ala Asn Val Gly Ser His Cys Asp Leu Ser 2150 2155 2160 Leu Lys Ile Pro Glu Ile Ser Ile Gln Asp Met Thr Ala Gln Val 2165 2170 2175 Thr Ser Pro Ser Gly Lys Thr His Glu Ala Glu Ile Val Glu Gly 2180 2185 2190 Glu Asn His Thr Tyr Cys Ile Arg Phe Val Pro Ala Glu Met Gly 2195 2200 2205 Thr His Thr Val Ser Val Lys Tyr Lys Gly Gln His Val Pro Gly 2210 2215 2220 Ser Pro Phe Gln Phe Thr Val Gly Pro Leu Gly Glu Gly Gly Ala 2225 2230 2235 His Lys Val Arg Ala Gly Gly Pro Gly Leu Glu Arg Ala Glu Ala 2240 2245 2250 Gly Val Pro Ala Glu Phe Ser Ile Trp Thr Arg Glu Ala Gly Ala 2255 2260 2265 Gly Gly Leu Ala Ile Ala Val Glu Gly Pro Ser Lys Ala Glu Ile 2270 2275 2280 Ser Phe Glu Asp Arg Lys Asp Gly Ser Cys Gly Val Ala Tyr Val 2285 2290 2295 Val Gln Glu Pro Gly Asp Tyr Glu Val Ser Val Lys Phe Asn Glu 2300 2305 2310 Glu His Ile Pro Asp Ser Pro Phe Val Val Pro Val Ala Ser Pro 2315 2320 2325 Ser Gly Asp Ala Arg Arg Leu Thr Val Ser Ser Leu Gln Glu Ser 2330 2335 2340 Gly Leu Lys Val Asn Gln Pro Ala Ser Phe Ala Val Ser Leu Asn 2345 2350 2355 Gly Ala Lys Gly Ala Ile Asp Ala Lys Val His Ser Pro Ser Gly 2360 2365 2370 Ala Leu Glu Glu Cys Tyr Val Thr Glu Ile Asp Gln Asp Lys Tyr 2375 2380 2385 Ala Val Arg Phe Ile Pro Arg Glu Asn Gly Val Tyr Leu Ile Asp 2390 2395 2400 Val Lys Phe Asn Gly Thr His Ile Pro Gly Ser Pro Phe Lys Ile 2405 2410 2415 Arg Val Gly Glu Pro Gly His Gly Gly Asp Pro Gly Leu Val Ser 2420 2425 2430 Ala Tyr Gly Ala Gly Leu Glu Gly Gly Val Thr Gly Asn Pro Ala 2435 2440 2445 Glu Phe Val Val Asn Thr Ser Asn Ala Gly Ala Gly Ala Leu Ser 2450 2455 2460 Val Thr Ile Asp Gly Pro Ser Lys Val Lys Met Asp Cys Gln Glu 2465 2470 2475 Cys Pro Glu Gly Tyr Arg Val Thr Tyr Thr Pro Met Ala Pro Gly 2480 2485 2490 Ser Tyr Leu Ile Ser Ile Lys Tyr Gly Gly Pro Tyr His Ile Gly 2495 2500 2505 Gly Ser Pro Phe Lys Ala Lys Val Thr Gly Pro Arg Leu Val Ser 2510 2515 2520 Asn His Ser Leu His Glu Thr Ser Ser Val Phe Val Asp Ser Leu 2525 2530 2535 Thr Lys Ala Thr Cys Ala Pro Gln His Gly Ala Pro Gly Pro Gly 2540 2545 2550 Pro Ala Asp Ala Ser Lys Val Val Ala Lys Gly Leu Gly Leu Ser 2555 2560 2565 Lys Ala Tyr Val Gly Gln Lys Ser Ser Phe Thr Val Asp Cys Ser 2570 2575 2580 Lys Ala Gly Asn Asn Met Leu Leu Val Gly Val His Gly Pro Arg 2585 2590 2595 Thr Pro Cys Glu Glu Ile Leu Val Lys His Val Gly Ser Arg Leu 2600 2605 2610 Tyr Ser Val Ser Tyr Leu Leu Lys Asp Lys Gly Glu Tyr Thr Leu 2615 2620 2625 Val Val Lys Trp Gly Asp Glu His Ile Pro Gly Ser Pro Tyr Arg 2630 2635 2640 Val Val Val Pro 2645 89320PRTHomo sapiens 89Met Ala Gln Val Leu Arg Gly Thr Val Thr Asp Phe Pro Gly Phe Asp 1 5 10 15 Glu Arg Ala Asp Ala Glu Thr Leu Arg Lys Ala Met Lys Gly Leu Gly 20 25 30 Thr Asp Glu Glu Ser Ile Leu Thr Leu Leu Thr Ser Arg Ser Asn Ala 35 40 45 Gln Arg Gln Glu Ile Ser Ala Ala Phe Lys Thr Leu Phe Gly Arg Asp 50 55 60 Leu Leu Asp Asp Leu Lys Ser Glu Leu Thr Gly Lys Phe Glu Lys Leu 65 70 75 80 Ile Val Ala Leu Met Lys Pro Ser Arg Leu Tyr Asp Ala Tyr Glu Leu 85 90 95 Lys His Ala Leu Lys Gly Ala Gly Thr Asn Glu Lys Val Leu Thr Glu 100 105 110 Ile Ile Ala Ser Arg Thr Pro Glu Glu Leu Arg Ala Ile Lys Gln Val 115 120 125 Tyr Glu Glu Glu Tyr Gly Ser Ser Leu Glu Asp Asp Val Val Gly Asp 130 135 140 Thr Ser Gly Tyr Tyr Gln Arg Met Leu Val Val Leu Leu Gln Ala Asn 145 150 155 160 Arg Asp Pro Asp Ala Gly Ile Asp Glu Ala Gln Val Glu Gln Asp Ala 165 170 175 Gln Ala Leu Phe Gln Ala Gly Glu Leu Lys Trp Gly Thr Asp Glu Glu 180 185 190 Lys Phe Ile Thr Ile Phe Gly Thr Arg Ser Val Ser His Leu Arg Lys 195 200 205 Val Phe Asp Lys Tyr Met Thr Ile Ser Gly Phe Gln Ile Glu Glu Thr 210 215 220 Ile Asp Arg Glu Thr Ser Gly Asn Leu Glu Gln Leu Leu Leu Ala Val 225 230 235 240 Val Lys Ser Ile Arg Ser Ile Pro Ala Tyr Leu Ala Glu Thr Leu Tyr 245 250 255 Tyr Ala Met Lys Gly Ala Gly Thr Asp Asp His Thr Leu Ile Arg Val 260 265 270 Met Val Ser Arg Ser Glu Ile Asp Leu Phe Asn Ile Arg Lys Glu Phe 275 280 285 Arg Lys Asn Phe Ala Thr Ser Leu Tyr Ser Met Ile Lys Gly Asp Thr 290 295 300 Ser Gly Asp Tyr Lys Lys Ala Leu Leu Leu Leu Cys Gly Glu Asp Asp 305 310 315 320 9069PRTHomo sapiens 90Met Asp Thr Ser Arg Val Gln Pro Ile Lys Leu Ala Arg Val Thr Lys 1 5 10 15 Val Leu Gly Arg Thr Gly Ser Gln Gly Gln Cys Thr Gln Val Arg Val 20 25 30 Glu Phe Met Asp Asp Thr Ser Arg Ser Ile Ile Arg Asn Val Lys Gly 35 40 45 Pro Val Arg Glu Gly Asp Val Leu Thr Leu Leu Glu Ser Glu Arg Glu 50 55 60 Ala Arg Arg Leu Arg 65 91317PRTHomo sapiens 91Met Pro Arg Glu Asp Arg Ala Thr Trp Lys Ser Asn Tyr Phe Leu Lys 1 5 10 15 Ile Ile Gln Leu Leu Asp Asp Tyr Pro Lys Cys Phe Ile Val Gly Ala 20 25 30 Asp Asn Val Gly Ser Lys Gln Met Gln Gln Ile Arg Met Ser Leu Arg 35 40 45 Gly Lys Ala Val Val Leu Met Gly Lys Asn Thr Met Met Arg Lys Ala 50 55

60 Ile Arg Gly His Leu Glu Asn Asn Pro Ala Leu Glu Lys Leu Leu Pro 65 70 75 80 His Ile Arg Gly Asn Val Gly Phe Val Phe Thr Lys Glu Asp Leu Thr 85 90 95 Glu Ile Arg Asp Met Leu Leu Ala Asn Lys Val Pro Ala Ala Ala Arg 100 105 110 Ala Gly Ala Ile Ala Pro Cys Glu Val Thr Val Pro Ala Gln Asn Thr 115 120 125 Gly Leu Gly Pro Glu Lys Thr Ser Phe Phe Gln Ala Leu Gly Ile Thr 130 135 140 Thr Lys Ile Ser Arg Gly Thr Ile Glu Ile Leu Ser Asp Val Gln Leu 145 150 155 160 Ile Lys Thr Gly Asp Lys Val Gly Ala Ser Glu Ala Thr Leu Leu Asn 165 170 175 Met Leu Asn Ile Ser Pro Phe Ser Phe Gly Leu Val Ile Gln Gln Val 180 185 190 Phe Asp Asn Gly Ser Ile Tyr Asn Pro Glu Val Leu Asp Ile Thr Glu 195 200 205 Glu Thr Leu His Ser Arg Phe Leu Glu Gly Val Arg Asn Val Ala Ser 210 215 220 Val Cys Leu Gln Ile Gly Tyr Pro Thr Val Ala Ser Val Pro His Ser 225 230 235 240 Ile Ile Asn Gly Tyr Lys Arg Val Leu Ala Leu Ser Val Glu Thr Asp 245 250 255 Tyr Thr Phe Pro Leu Ala Glu Lys Val Lys Ala Phe Leu Ala Asp Pro 260 265 270 Ser Ala Phe Val Ala Ala Ala Pro Val Ala Ala Ala Thr Thr Ala Ala 275 280 285 Pro Ala Ala Ala Ala Ala Pro Ala Lys Val Glu Ala Lys Glu Glu Ser 290 295 300 Glu Glu Ser Asp Glu Asp Met Gly Phe Gly Leu Phe Asp 305 310 315 923335PRTHomo sapiens 92Met Ala Ala Ala Ala Arg Pro Arg Gly Arg Ala Leu Gly Pro Val Leu 1 5 10 15 Pro Pro Thr Pro Leu Leu Leu Leu Val Leu Arg Val Leu Pro Ala Cys 20 25 30 Gly Ala Thr Ala Arg Asp Pro Gly Ala Ala Ala Gly Leu Ser Leu His 35 40 45 Pro Thr Tyr Phe Asn Leu Ala Glu Ala Ala Arg Ile Trp Ala Thr Ala 50 55 60 Thr Cys Gly Glu Arg Gly Pro Gly Glu Gly Arg Pro Gln Pro Glu Leu 65 70 75 80 Tyr Cys Lys Leu Val Gly Gly Pro Thr Ala Pro Gly Ser Gly His Thr 85 90 95 Ile Gln Gly Gln Phe Cys Asp Tyr Cys Asn Ser Glu Asp Pro Arg Lys 100 105 110 Ala His Pro Val Thr Asn Ala Ile Asp Gly Ser Glu Arg Trp Trp Gln 115 120 125 Ser Pro Pro Leu Ser Ser Gly Thr Gln Tyr Asn Arg Val Asn Leu Thr 130 135 140 Leu Asp Leu Gly Gln Leu Phe His Val Ala Tyr Ile Leu Ile Lys Phe 145 150 155 160 Ala Asn Ser Pro Arg Pro Asp Leu Trp Val Leu Glu Arg Ser Val Asp 165 170 175 Phe Gly Ser Thr Tyr Ser Pro Trp Gln Tyr Phe Ala His Ser Lys Val 180 185 190 Asp Cys Leu Lys Glu Phe Gly Arg Glu Ala Asn Met Ala Val Thr Arg 195 200 205 Asp Asp Asp Val Leu Cys Val Thr Glu Tyr Ser Arg Ile Val Pro Leu 210 215 220 Glu Asn Gly Glu Val Val Val Ser Leu Ile Asn Gly Arg Pro Gly Ala 225 230 235 240 Lys Asn Phe Thr Phe Ser His Thr Leu Arg Glu Phe Thr Lys Ala Thr 245 250 255 Asn Ile Arg Leu Arg Phe Leu Arg Thr Asn Thr Leu Leu Gly His Leu 260 265 270 Ile Ser Lys Ala Gln Arg Asp Pro Thr Val Thr Arg Arg Tyr Tyr Tyr 275 280 285 Ser Ile Lys Asp Ile Ser Ile Gly Gly Gln Cys Val Cys Asn Gly His 290 295 300 Ala Glu Val Cys Asn Ile Asn Asn Pro Glu Lys Leu Phe Arg Cys Glu 305 310 315 320 Cys Gln His His Thr Cys Gly Glu Thr Cys Asp Arg Cys Cys Thr Gly 325 330 335 Tyr Asn Gln Arg Arg Trp Arg Pro Ala Ala Trp Glu Gln Ser His Glu 340 345 350 Cys Glu Ala Cys Asn Cys His Gly His Ala Ser Asn Cys Tyr Tyr Asp 355 360 365 Pro Asp Val Glu Arg Gln Gln Ala Ser Leu Asn Thr Gln Gly Ile Tyr 370 375 380 Ala Gly Gly Gly Val Cys Ile Asn Cys Gln His Asn Thr Ala Gly Val 385 390 395 400 Asn Cys Glu Gln Cys Ala Lys Gly Tyr Tyr Arg Pro Tyr Gly Val Pro 405 410 415 Val Asp Ala Pro Asp Gly Cys Ile Pro Cys Ser Cys Asp Pro Glu His 420 425 430 Ala Asp Gly Cys Glu Gln Gly Ser Gly Arg Cys His Cys Lys Pro Asn 435 440 445 Phe His Gly Asp Asn Cys Glu Lys Cys Ala Ile Gly Tyr Tyr Asn Phe 450 455 460 Pro Phe Cys Leu Arg Ile Pro Ile Phe Pro Val Ser Thr Pro Ser Ser 465 470 475 480 Glu Asp Pro Val Ala Gly Asp Ile Lys Gly Asn Trp Cys Asp Cys Asn 485 490 495 Leu Glu Gly Val Leu Pro Glu Ile Cys Asp Ala His Gly Arg Cys Leu 500 505 510 Cys Arg Pro Gly Val Glu Gly Pro Arg Cys Asp Thr Cys Arg Ser Gly 515 520 525 Phe Tyr Ser Phe Pro Ile Cys Gln Ala Cys Trp Cys Ser Ala Leu Gly 530 535 540 Ser Tyr Gln Met Pro Cys Ser Ser Val Thr Gly Gln Cys Glu Cys Arg 545 550 555 560 Pro Gly Val Thr Gly Gln Arg Cys Asp Arg Cys Leu Ser Gly Ala Tyr 565 570 575 Asp Phe Pro His Cys Gln Gly Ser Ser Ser Ala Cys Asp Pro Ala Gly 580 585 590 Thr Ile Asn Ser Asn Leu Gly Tyr Cys Gln Cys Lys Leu His Val Glu 595 600 605 Gly Pro Thr Cys Ser Arg Cys Lys Leu Leu Tyr Trp Asn Leu Asp Lys 610 615 620 Glu Asn Pro Ser Gly Cys Ser Glu Cys Lys Cys His Lys Ala Gly Thr 625 630 635 640 Val Ser Gly Thr Gly Glu Cys Arg Gln Gly Asp Gly Asp Cys His Cys 645 650 655 Lys Ser His Val Gly Gly Asp Ser Cys Asp Thr Cys Glu Asp Gly Tyr 660 665 670 Phe Ala Leu Glu Lys Ser Asn Tyr Phe Gly Cys Gln Gly Cys Gln Cys 675 680 685 Asp Ile Gly Gly Ala Leu Ser Ser Met Cys Ser Gly Pro Ser Gly Val 690 695 700 Cys Gln Cys Arg Glu His Val Val Gly Lys Val Cys Gln Arg Pro Glu 705 710 715 720 Asn Asn Tyr Tyr Phe Pro Asp Leu His His Met Lys Tyr Glu Ile Glu 725 730 735 Asp Gly Ser Thr Pro Asn Gly Arg Asp Leu Arg Phe Gly Phe Asp Pro 740 745 750 Leu Ala Phe Pro Glu Phe Ser Trp Arg Gly Tyr Ala Gln Met Thr Ser 755 760 765 Val Gln Asn Asp Val Arg Ile Thr Leu Asn Val Gly Lys Ser Ser Gly 770 775 780 Ser Leu Phe Arg Val Ile Leu Arg Tyr Val Asn Pro Gly Thr Glu Ala 785 790 795 800 Val Ser Gly His Ile Thr Ile Tyr Pro Ser Trp Gly Ala Ala Gln Ser 805 810 815 Lys Glu Ile Ile Phe Leu Pro Ser Lys Glu Pro Ala Phe Val Thr Val 820 825 830 Pro Gly Asn Gly Phe Ala Asp Pro Phe Ser Ile Thr Pro Gly Ile Trp 835 840 845 Val Ala Cys Ile Lys Ala Glu Gly Val Leu Leu Asp Tyr Leu Val Leu 850 855 860 Leu Pro Arg Asp Tyr Tyr Glu Ala Ser Val Leu Gln Leu Pro Val Thr 865 870 875 880 Glu Pro Cys Ala Tyr Ala Gly Pro Pro Gln Glu Asn Cys Leu Leu Tyr 885 890 895 Gln His Leu Pro Val Thr Arg Phe Pro Cys Thr Leu Ala Cys Glu Ala 900 905 910 Arg His Phe Leu Leu Asp Gly Glu Pro Arg Pro Val Ala Val Arg Gln 915 920 925 Pro Thr Pro Ala His Pro Val Met Val Asp Leu Ser Gly Arg Glu Val 930 935 940 Glu Leu His Leu Arg Leu Arg Ile Pro Gln Val Gly His Tyr Val Val 945 950 955 960 Val Val Glu Tyr Ser Thr Glu Ala Ala Gln Leu Phe Val Val Asp Val 965 970 975 Asn Val Lys Ser Ser Gly Ser Val Leu Ala Gly Gln Val Asn Ile Tyr 980 985 990 Ser Cys Asn Tyr Ser Val Leu Cys Arg Ser Ala Val Ile Asp His Met 995 1000 1005 Ser Arg Ile Ala Met Tyr Glu Leu Leu Ala Asp Ala Asp Ile Gln 1010 1015 1020 Leu Lys Gly His Met Ala Arg Phe Leu Leu His Gln Val Cys Ile 1025 1030 1035 Ile Pro Ile Glu Glu Phe Ser Ala Glu Tyr Val Arg Pro Gln Val 1040 1045 1050 His Cys Ile Ala Ser Tyr Gly Arg Phe Val Asn Gln Ser Ala Thr 1055 1060 1065 Cys Val Ser Leu Ala His Glu Thr Pro Pro Thr Ala Leu Ile Leu 1070 1075 1080 Asp Val Leu Ser Gly Arg Pro Phe Pro His Leu Pro Gln Gln Ser 1085 1090 1095 Ser Pro Ser Val Asp Val Leu Pro Gly Val Thr Leu Lys Ala Pro 1100 1105 1110 Gln Asn Gln Val Thr Leu Arg Gly Arg Val Pro His Leu Gly Arg 1115 1120 1125 Tyr Val Phe Val Ile His Phe Tyr Gln Ala Ala His Pro Thr Phe 1130 1135 1140 Pro Ala Gln Val Ser Val Asp Gly Gly Trp Pro Arg Ala Gly Ser 1145 1150 1155 Phe His Ala Ser Phe Cys Pro His Val Leu Gly Cys Arg Asp Gln 1160 1165 1170 Val Ile Ala Glu Gly Gln Ile Glu Phe Asp Ile Ser Glu Pro Glu 1175 1180 1185 Val Ala Ala Thr Val Lys Val Pro Glu Gly Lys Ser Leu Val Leu 1190 1195 1200 Val Arg Val Leu Val Val Pro Ala Glu Asn Tyr Asp Tyr Gln Ile 1205 1210 1215 Leu His Lys Lys Ser Met Asp Lys Ser Leu Glu Phe Ile Thr Asn 1220 1225 1230 Cys Gly Lys Asn Ser Phe Tyr Leu Asp Pro Gln Thr Ala Ser Arg 1235 1240 1245 Phe Cys Lys Asn Ser Ala Arg Ser Leu Val Ala Phe Tyr His Lys 1250 1255 1260 Gly Ala Leu Pro Cys Glu Cys His Pro Thr Gly Ala Thr Gly Pro 1265 1270 1275 His Cys Ser Pro Glu Gly Gly Gln Cys Pro Cys Gln Pro Asn Val 1280 1285 1290 Ile Gly Arg Gln Cys Thr Arg Cys Ala Thr Gly His Tyr Gly Phe 1295 1300 1305 Pro Arg Cys Lys Pro Cys Ser Cys Gly Arg Arg Leu Cys Glu Glu 1310 1315 1320 Met Thr Gly Gln Cys Arg Cys Pro Pro Arg Thr Val Arg Pro Gln 1325 1330 1335 Cys Glu Val Cys Glu Thr His Ser Phe Ser Phe His Pro Met Ala 1340 1345 1350 Gly Cys Glu Gly Cys Asn Cys Ser Arg Arg Gly Thr Ile Glu Ala 1355 1360 1365 Ala Met Pro Glu Cys Asp Arg Asp Ser Gly Gln Cys Arg Cys Lys 1370 1375 1380 Pro Arg Ile Thr Gly Arg Gln Cys Asp Arg Cys Ala Ser Gly Phe 1385 1390 1395 Tyr Arg Phe Pro Glu Cys Val Pro Cys Asn Cys Asn Arg Asp Gly 1400 1405 1410 Thr Glu Pro Gly Val Cys Asp Pro Gly Thr Gly Ala Cys Leu Cys 1415 1420 1425 Lys Glu Asn Val Glu Gly Thr Glu Cys Asn Val Cys Arg Glu Gly 1430 1435 1440 Ser Phe His Leu Asp Pro Ala Asn Leu Lys Gly Cys Thr Ser Cys 1445 1450 1455 Phe Cys Phe Gly Val Asn Asn Gln Cys His Ser Ser His Lys Arg 1460 1465 1470 Arg Thr Lys Phe Val Asp Met Leu Gly Trp His Leu Glu Thr Ala 1475 1480 1485 Asp Arg Val Asp Ile Pro Val Ser Phe Asn Pro Gly Ser Asn Ser 1490 1495 1500 Met Val Ala Asp Leu Gln Glu Leu Pro Ala Thr Ile His Ser Ala 1505 1510 1515 Ser Trp Val Ala Pro Thr Ser Tyr Leu Gly Asp Lys Val Ser Ser 1520 1525 1530 Tyr Gly Gly Tyr Leu Thr Tyr Gln Ala Lys Ser Phe Gly Leu Pro 1535 1540 1545 Gly Asp Met Val Leu Leu Glu Lys Lys Pro Asp Val Gln Leu Thr 1550 1555 1560 Gly Gln His Met Ser Ile Ile Tyr Glu Glu Thr Asn Thr Pro Arg 1565 1570 1575 Pro Asp Arg Leu His His Gly Arg Val His Val Val Glu Gly Asn 1580 1585 1590 Phe Arg His Ala Ser Ser Arg Ala Pro Val Ser Arg Glu Glu Leu 1595 1600 1605 Met Thr Val Leu Ser Arg Leu Ala Asp Val Arg Ile Gln Gly Leu 1610 1615 1620 Tyr Phe Thr Glu Thr Gln Arg Leu Thr Leu Ser Glu Val Gly Leu 1625 1630 1635 Glu Glu Ala Ser Asp Thr Gly Ser Gly Arg Ile Ala Leu Ala Val 1640 1645 1650 Glu Ile Cys Ala Cys Pro Pro Ala Tyr Ala Gly Asp Ser Cys Gln 1655 1660 1665 Gly Cys Ser Pro Gly Tyr Tyr Arg Asp His Lys Gly Leu Tyr Thr 1670 1675 1680 Gly Arg Cys Val Pro Cys Asn Cys Asn Gly His Ser Asn Gln Cys 1685 1690 1695 Gln Asp Gly Ser Gly Ile Cys Val Asn Cys Gln His Asn Thr Ala 1700 1705 1710 Gly Glu His Cys Glu Arg Cys Gln Glu Gly Tyr Tyr Gly Asn Ala 1715 1720 1725 Val His Gly Ser Cys Arg Ala Cys Pro Cys Pro His Thr Asn Ser 1730 1735 1740 Phe Ala Thr Gly Cys Val Val Asn Gly Gly Asp Val Arg Cys Ser 1745 1750 1755 Cys Lys Ala Gly Tyr Thr Gly Thr Gln Cys Glu Arg Cys Ala Pro 1760 1765 1770 Gly Tyr Phe Gly Asn Pro Gln Lys Phe Gly Gly Ser Cys Gln Pro 1775 1780 1785 Cys Ser Cys Asn Ser Asn Gly Gln Leu Gly Ser Cys His Pro Leu 1790 1795 1800 Thr Gly Asp Cys Ile Asn Gln Glu Pro Lys Asp Ser Ser Pro Ala 1805 1810 1815 Glu Glu Cys Asp Asp Cys Asp Ser Cys Val Met Thr Leu Leu Asn 1820 1825 1830 Asp Leu Ala Thr Met Gly Glu Gln Leu Arg Leu Val Lys Ser Gln 1835 1840 1845 Leu Gln Gly Leu Ser Ala Ser Ala Gly Leu Leu Glu Gln Met Arg 1850 1855 1860 His Met Glu Thr Gln Ala Lys Asp Leu Arg Asn Gln Leu Leu Asn 1865 1870 1875 Tyr Arg Ser Ala Ile Ser Asn His Gly Ser Lys Ile Glu Gly Leu 1880 1885 1890 Glu Arg Glu Leu Thr Asp Leu Asn Gln Glu Phe Glu Thr Leu Gln 1895 1900 1905 Glu Lys Ala Gln Val Asn Ser Arg Lys Ala Gln Thr Leu Asn Asn 1910 1915 1920 Asn Val Asn Arg Ala Thr Gln Ser Ala Lys Glu Leu Asp Val Lys 1925 1930 1935 Ile Lys Asn Val Ile Arg Asn Val His Ile Leu Leu Lys Gln Ile 1940 1945 1950 Ser Gly Thr Asp Gly Glu Gly Asn Asn Val Pro Ser Gly Asp Phe 1955 1960 1965 Ser Arg Glu Trp Ala Glu Ala Gln Arg Met Met Arg Glu Leu Arg 1970 1975 1980 Asn Arg Asn Phe Gly Lys His Leu Arg Glu Ala Glu Ala Asp Lys 1985 1990 1995

Arg Glu Ser Gln Leu Leu Leu Asn Arg Ile Arg Thr Trp Gln Lys 2000 2005 2010 Thr His Gln Gly Glu Asn Asn Gly Leu Ala Asn Ser Ile Arg Asp 2015 2020 2025 Ser Leu Asn Glu Tyr Glu Ala Lys Leu Ser Asp Leu Arg Ala Arg 2030 2035 2040 Leu Gln Glu Ala Ala Ala Gln Ala Lys Gln Ala Asn Gly Leu Asn 2045 2050 2055 Gln Glu Asn Glu Arg Ala Leu Gly Ala Ile Gln Arg Gln Val Lys 2060 2065 2070 Glu Ile Asn Ser Leu Gln Ser Asp Phe Thr Lys Tyr Leu Thr Thr 2075 2080 2085 Ala Asp Ser Ser Leu Leu Gln Thr Asn Ile Ala Leu Gln Leu Met 2090 2095 2100 Glu Lys Ser Gln Lys Glu Tyr Glu Lys Leu Ala Ala Ser Leu Asn 2105 2110 2115 Glu Ala Arg Gln Glu Leu Ser Asp Lys Val Arg Glu Leu Ser Arg 2120 2125 2130 Ser Ala Gly Lys Thr Ser Leu Val Glu Glu Ala Glu Lys His Ala 2135 2140 2145 Arg Ser Leu Gln Glu Leu Ala Lys Gln Leu Glu Glu Ile Lys Arg 2150 2155 2160 Asn Ala Ser Gly Asp Glu Leu Val Arg Cys Ala Val Asp Ala Ala 2165 2170 2175 Thr Ala Tyr Glu Asn Ile Leu Asn Ala Ile Lys Ala Ala Glu Asp 2180 2185 2190 Ala Ala Asn Arg Ala Ala Ser Ala Ser Glu Ser Ala Leu Gln Thr 2195 2200 2205 Val Ile Lys Glu Asp Leu Pro Arg Lys Ala Lys Thr Leu Ser Ser 2210 2215 2220 Asn Ser Asp Lys Leu Leu Asn Glu Ala Lys Met Thr Gln Lys Lys 2225 2230 2235 Leu Lys Gln Glu Val Ser Pro Ala Leu Asn Asn Leu Gln Gln Thr 2240 2245 2250 Leu Asn Ile Val Thr Val Gln Lys Glu Val Ile Asp Thr Asn Leu 2255 2260 2265 Thr Thr Leu Arg Asp Gly Leu His Gly Ile Gln Arg Gly Asp Ile 2270 2275 2280 Asp Ala Met Ile Ser Ser Ala Lys Ser Met Val Arg Lys Ala Asn 2285 2290 2295 Asp Ile Thr Asp Glu Val Leu Asp Gly Leu Asn Pro Ile Gln Thr 2300 2305 2310 Asp Val Glu Arg Ile Lys Asp Thr Tyr Gly Arg Thr Gln Asn Glu 2315 2320 2325 Asp Phe Lys Lys Ala Leu Thr Asp Ala Asp Asn Ser Val Asn Lys 2330 2335 2340 Leu Thr Asn Lys Leu Pro Asp Leu Trp Arg Lys Ile Glu Ser Ile 2345 2350 2355 Asn Gln Gln Leu Leu Pro Leu Gly Asn Ile Ser Asp Asn Met Asp 2360 2365 2370 Arg Ile Arg Glu Leu Ile Gln Gln Ala Arg Asp Ala Ala Ser Lys 2375 2380 2385 Val Ala Val Pro Met Arg Phe Asn Gly Lys Ser Gly Val Glu Val 2390 2395 2400 Arg Leu Pro Asn Asp Leu Glu Asp Leu Lys Gly Tyr Thr Ser Leu 2405 2410 2415 Ser Leu Phe Leu Gln Arg Pro Asn Ser Arg Glu Asn Gly Gly Thr 2420 2425 2430 Glu Asn Met Phe Val Met Tyr Leu Gly Asn Lys Asp Ala Ser Arg 2435 2440 2445 Asp Tyr Ile Gly Met Ala Val Val Asp Gly Gln Leu Thr Cys Val 2450 2455 2460 Tyr Asn Leu Gly Asp Arg Glu Ala Glu Leu Gln Val Asp Gln Ile 2465 2470 2475 Leu Thr Lys Ser Glu Thr Lys Glu Ala Val Met Asp Arg Val Lys 2480 2485 2490 Phe Gln Arg Ile Tyr Gln Phe Ala Arg Leu Asn Tyr Thr Lys Gly 2495 2500 2505 Ala Thr Ser Ser Lys Pro Glu Thr Pro Gly Val Tyr Asp Met Asp 2510 2515 2520 Gly Arg Asn Ser Asn Thr Leu Leu Asn Leu Asp Pro Glu Asn Val 2525 2530 2535 Val Phe Tyr Val Gly Gly Tyr Pro Pro Asp Phe Lys Leu Pro Ser 2540 2545 2550 Arg Leu Ser Phe Pro Pro Tyr Lys Gly Cys Ile Glu Leu Asp Asp 2555 2560 2565 Leu Asn Glu Asn Val Leu Ser Leu Tyr Asn Phe Lys Lys Thr Phe 2570 2575 2580 Asn Leu Asn Thr Thr Glu Val Glu Pro Cys Arg Arg Arg Lys Glu 2585 2590 2595 Glu Ser Asp Lys Asn Tyr Phe Glu Gly Thr Gly Tyr Ala Arg Val 2600 2605 2610 Pro Thr Gln Pro His Ala Pro Ile Pro Thr Phe Gly Gln Thr Ile 2615 2620 2625 Gln Thr Thr Val Asp Arg Gly Leu Leu Phe Phe Ala Glu Asn Gly 2630 2635 2640 Asp Arg Phe Ile Ser Leu Asn Ile Glu Asp Gly Lys Leu Met Val 2645 2650 2655 Arg Tyr Lys Leu Asn Ser Glu Leu Pro Lys Glu Arg Gly Val Gly 2660 2665 2670 Asp Ala Ile Asn Asn Gly Arg Asp His Ser Ile Gln Ile Lys Ile 2675 2680 2685 Gly Lys Leu Gln Lys Arg Met Trp Ile Asn Val Asp Val Gln Asn 2690 2695 2700 Thr Ile Ile Asp Gly Glu Val Phe Asp Phe Ser Thr Tyr Tyr Leu 2705 2710 2715 Gly Gly Ile Pro Ile Ala Ile Arg Glu Arg Phe Asn Ile Ser Thr 2720 2725 2730 Pro Ala Phe Arg Gly Cys Met Lys Asn Leu Lys Lys Thr Ser Gly 2735 2740 2745 Val Val Arg Leu Asn Asp Thr Val Gly Val Thr Lys Lys Cys Ser 2750 2755 2760 Glu Asp Trp Lys Leu Val Arg Ser Ala Ser Phe Ser Arg Gly Gly 2765 2770 2775 Gln Leu Ser Phe Thr Asp Leu Gly Leu Pro Pro Thr Asp His Leu 2780 2785 2790 Gln Ala Ser Phe Gly Phe Gln Thr Phe Gln Pro Ser Gly Ile Leu 2795 2800 2805 Leu Asp His Gln Thr Trp Thr Arg Asn Leu Gln Val Thr Leu Glu 2810 2815 2820 Asp Gly Tyr Ile Glu Leu Ser Thr Ser Asp Ser Gly Ser Pro Ile 2825 2830 2835 Phe Lys Ser Pro Gln Thr Tyr Met Asp Gly Leu Leu His Tyr Val 2840 2845 2850 Ser Val Ile Ser Asp Asn Ser Gly Leu Arg Leu Leu Ile Asp Asp 2855 2860 2865 Gln Leu Leu Arg Asn Ser Lys Arg Leu Lys His Ile Ser Ser Ser 2870 2875 2880 Arg Gln Ser Leu Arg Leu Gly Gly Ser Asn Phe Glu Gly Cys Ile 2885 2890 2895 Ser Asn Val Phe Val Gln Arg Leu Ser Leu Ser Pro Glu Val Leu 2900 2905 2910 Asp Leu Thr Ser Asn Ser Leu Lys Arg Asp Val Ser Leu Gly Gly 2915 2920 2925 Cys Ser Leu Asn Lys Pro Pro Phe Leu Met Leu Leu Lys Gly Ser 2930 2935 2940 Thr Arg Phe Asn Lys Thr Lys Thr Phe Arg Ile Asn Gln Leu Leu 2945 2950 2955 Gln Asp Thr Pro Val Ala Ser Pro Arg Ser Val Lys Val Trp Gln 2960 2965 2970 Asp Ala Cys Ser Pro Leu Pro Lys Thr Gln Ala Asn His Gly Ala 2975 2980 2985 Leu Gln Phe Gly Asp Ile Pro Thr Ser His Leu Leu Phe Lys Leu 2990 2995 3000 Pro Gln Glu Leu Leu Lys Pro Arg Ser Gln Phe Ala Val Asp Met 3005 3010 3015 Gln Thr Thr Ser Ser Arg Gly Leu Val Phe His Thr Gly Thr Lys 3020 3025 3030 Asn Ser Phe Met Ala Leu Tyr Leu Ser Lys Gly Arg Leu Val Phe 3035 3040 3045 Ala Leu Gly Thr Asp Gly Lys Lys Leu Arg Ile Lys Ser Lys Glu 3050 3055 3060 Lys Cys Asn Asp Gly Lys Trp His Thr Val Val Phe Gly His Asp 3065 3070 3075 Gly Glu Lys Gly Arg Leu Val Val Asp Gly Leu Arg Ala Arg Glu 3080 3085 3090 Gly Ser Leu Pro Gly Asn Ser Thr Ile Ser Ile Arg Ala Pro Val 3095 3100 3105 Tyr Leu Gly Ser Pro Pro Ser Gly Lys Pro Lys Ser Leu Pro Thr 3110 3115 3120 Asn Ser Phe Val Gly Cys Leu Lys Asn Phe Gln Leu Asp Ser Lys 3125 3130 3135 Pro Leu Tyr Thr Pro Ser Ser Ser Phe Gly Val Ser Ser Cys Leu 3140 3145 3150 Gly Gly Pro Leu Glu Lys Gly Ile Tyr Phe Ser Glu Glu Gly Gly 3155 3160 3165 His Val Val Leu Ala His Ser Val Leu Leu Gly Pro Glu Phe Lys 3170 3175 3180 Leu Val Phe Ser Ile Arg Pro Arg Ser Leu Thr Gly Ile Leu Ile 3185 3190 3195 His Ile Gly Ser Gln Pro Gly Lys His Leu Cys Val Tyr Leu Glu 3200 3205 3210 Ala Gly Lys Val Thr Ala Ser Met Asp Ser Gly Ala Gly Gly Thr 3215 3220 3225 Ser Thr Ser Val Thr Pro Lys Gln Ser Leu Cys Asp Gly Gln Trp 3230 3235 3240 His Ser Val Ala Val Thr Ile Lys Gln His Ile Leu His Leu Glu 3245 3250 3255 Leu Asp Thr Asp Ser Ser Tyr Thr Ala Gly Gln Ile Pro Phe Pro 3260 3265 3270 Pro Ala Ser Thr Gln Glu Pro Leu His Leu Gly Gly Ala Pro Ala 3275 3280 3285 Asn Leu Thr Thr Leu Arg Ile Pro Val Trp Lys Ser Phe Phe Gly 3290 3295 3300 Cys Leu Arg Asn Ile His Val Asn His Ile Pro Val Pro Val Thr 3305 3310 3315 Glu Ala Leu Glu Val Gln Gly Pro Val Ser Leu Asn Gly Cys Pro 3320 3325 3330 Asp Gln 3335 93128PRTHomo sapiens 93Met Ser Gly Arg Gly Lys Gln Gly Gly Lys Ala Arg Ala Lys Ala Lys 1 5 10 15 Thr Arg Ser Ser Arg Ala Gly Leu Gln Phe Pro Val Gly Arg Val His 20 25 30 Arg Leu Leu Arg Lys Gly Asn Tyr Ala Glu Arg Val Gly Ala Gly Ala 35 40 45 Pro Val Tyr Leu Ala Ala Val Leu Glu Tyr Leu Thr Ala Glu Ile Leu 50 55 60 Glu Leu Ala Gly Asn Ala Ala Arg Asp Asn Lys Lys Thr Arg Ile Ile 65 70 75 80 Pro Arg His Leu Gln Leu Ala Ile Arg Asn Asp Glu Glu Leu Asn Lys 85 90 95 Leu Leu Gly Lys Val Thr Ile Ala Gln Gly Gly Val Leu Pro Asn Ile 100 105 110 Gln Ala Val Leu Leu Pro Lys Lys Thr Glu Ser His His Lys Ala Lys 115 120 125 94406PRTHomo sapiens 94Met Ser Ala Ser Gln Asp Ser Arg Ser Arg Asp Asn Gly Pro Asp Gly 1 5 10 15 Met Glu Pro Glu Gly Val Ile Glu Ser Asn Trp Asn Glu Ile Val Asp 20 25 30 Ser Phe Asp Asp Met Asn Leu Ser Glu Ser Leu Leu Arg Gly Ile Tyr 35 40 45 Ala Tyr Gly Phe Glu Lys Pro Ser Ala Ile Gln Gln Arg Ala Ile Leu 50 55 60 Pro Cys Ile Lys Gly Tyr Asp Val Ile Ala Gln Ala Gln Ser Gly Thr 65 70 75 80 Gly Lys Thr Ala Thr Phe Ala Ile Ser Ile Leu Gln Gln Ile Glu Leu 85 90 95 Asp Leu Lys Ala Thr Gln Ala Leu Val Leu Ala Pro Thr Arg Glu Leu 100 105 110 Ala Gln Gln Ile Gln Lys Val Val Met Ala Leu Gly Asp Tyr Met Gly 115 120 125 Ala Ser Cys His Ala Cys Ile Gly Gly Thr Asn Val Arg Ala Glu Val 130 135 140 Gln Lys Leu Gln Met Glu Ala Pro His Ile Ile Val Gly Thr Pro Gly 145 150 155 160 Arg Val Phe Asp Met Leu Asn Arg Arg Tyr Leu Ser Pro Lys Tyr Ile 165 170 175 Lys Met Phe Val Leu Asp Glu Ala Asp Glu Met Leu Ser Arg Gly Phe 180 185 190 Lys Asp Gln Ile Tyr Asp Ile Phe Gln Lys Leu Asn Ser Asn Thr Gln 195 200 205 Val Val Leu Leu Ser Ala Thr Met Pro Ser Asp Val Leu Glu Val Thr 210 215 220 Lys Lys Phe Met Arg Asp Pro Ile Arg Ile Leu Val Lys Lys Glu Glu 225 230 235 240 Leu Thr Leu Glu Gly Ile Arg Gln Phe Tyr Ile Asn Val Glu Arg Glu 245 250 255 Glu Trp Lys Leu Asp Thr Leu Cys Asp Leu Tyr Glu Thr Leu Thr Ile 260 265 270 Thr Gln Ala Val Ile Phe Ile Asn Thr Arg Arg Lys Val Asp Trp Leu 275 280 285 Thr Glu Lys Met His Ala Arg Asp Phe Thr Val Ser Ala Met His Gly 290 295 300 Asp Met Asp Gln Lys Glu Arg Asp Val Ile Met Arg Glu Phe Arg Ser 305 310 315 320 Gly Ser Ser Arg Val Leu Ile Thr Thr Asp Leu Leu Ala Arg Gly Ile 325 330 335 Asp Val Gln Gln Val Ser Leu Val Ile Asn Tyr Asp Leu Pro Thr Asn 340 345 350 Arg Glu Asn Tyr Ile His Arg Ile Gly Arg Gly Gly Arg Phe Gly Arg 355 360 365 Lys Gly Val Ala Ile Asn Met Val Thr Glu Glu Asp Lys Arg Thr Leu 370 375 380 Arg Asp Ile Glu Thr Phe Tyr Asn Thr Ser Ile Glu Glu Met Pro Leu 385 390 395 400 Asn Val Ala Asp Leu Ile 405 95577PRTHomo sapiens 95Met Pro Lys Thr Ile Ser Val Arg Val Thr Thr Met Asp Ala Glu Leu 1 5 10 15 Glu Phe Ala Ile Gln Pro Asn Thr Thr Gly Lys Gln Leu Phe Asp Gln 20 25 30 Val Val Lys Thr Ile Gly Leu Arg Glu Val Trp Phe Phe Gly Leu Gln 35 40 45 Tyr Gln Asp Thr Lys Gly Phe Ser Thr Trp Leu Lys Leu Asn Lys Lys 50 55 60 Val Thr Ala Gln Asp Val Arg Lys Glu Ser Pro Leu Leu Phe Lys Phe 65 70 75 80 Arg Ala Lys Phe Tyr Pro Glu Asp Val Ser Glu Glu Leu Ile Gln Asp 85 90 95 Ile Thr Gln Arg Leu Phe Phe Leu Gln Val Lys Glu Gly Ile Leu Asn 100 105 110 Asp Asp Ile Tyr Cys Pro Pro Glu Thr Ala Val Leu Leu Ala Ser Tyr 115 120 125 Ala Val Gln Ser Lys Tyr Gly Asp Phe Asn Lys Glu Val His Lys Ser 130 135 140 Gly Tyr Leu Ala Gly Asp Lys Leu Leu Pro Gln Arg Val Leu Glu Gln 145 150 155 160 His Lys Leu Asn Lys Asp Gln Trp Glu Glu Arg Ile Gln Val Trp His 165 170 175 Glu Glu His Arg Gly Met Leu Arg Glu Asp Ala Val Leu Glu Tyr Leu 180 185 190 Lys Ile Ala Gln Asp Leu Glu Met Tyr Gly Val Asn Tyr Phe Ser Ile 195 200 205 Lys Asn Lys Lys Gly Ser Glu Leu Trp Leu Gly Val Asp Ala Leu Gly 210 215 220 Leu Asn Ile Tyr Glu Gln Asn Asp Arg Leu Thr Pro Lys Ile Gly Phe 225 230 235 240 Pro Trp Ser Glu Ile Arg Asn Ile Ser Phe Asn Asp Lys Lys Phe Val 245 250 255 Ile Lys Pro Ile Asp Lys Lys Ala Pro Asp Phe Val Phe Tyr Ala Pro 260 265 270 Arg Leu Arg Ile Asn Lys Arg Ile Leu Ala Leu Cys Met Gly Asn His 275 280 285 Glu Leu Tyr Met Arg Arg Arg Lys Pro Asp Thr Ile Glu Val Gln Gln 290 295 300 Met Lys Ala Gln Ala Arg Glu Glu Lys His Gln Lys Gln Met Glu Arg 305 310 315 320 Ala Met Leu Glu Asn Glu Lys Lys Lys Arg Glu Met Ala Glu Lys Glu 325 330 335 Lys Glu Lys Ile Glu Arg Glu Lys Glu Glu Leu Met Glu Arg Leu Lys 340 345 350 Gln Ile Glu Glu Gln Thr Lys Lys Ala Gln Gln Glu Leu Glu Glu Gln

355 360 365 Thr Arg Arg Ala Leu Glu Leu Glu Gln Glu Arg Lys Arg Ala Gln Ser 370 375 380 Glu Ala Glu Lys Leu Ala Lys Glu Arg Gln Glu Ala Glu Glu Ala Lys 385 390 395 400 Glu Ala Leu Leu Gln Ala Ser Arg Asp Gln Lys Lys Thr Gln Glu Gln 405 410 415 Leu Ala Leu Glu Met Ala Glu Leu Thr Ala Arg Ile Ser Gln Leu Glu 420 425 430 Met Ala Arg Gln Lys Lys Glu Ser Glu Ala Val Glu Trp Gln Gln Lys 435 440 445 Ala Gln Met Val Gln Glu Asp Leu Glu Lys Thr Arg Ala Glu Leu Lys 450 455 460 Thr Ala Met Ser Thr Pro His Val Ala Glu Pro Ala Glu Asn Glu Gln 465 470 475 480 Asp Glu Gln Asp Glu Asn Gly Ala Glu Ala Ser Ala Asp Leu Arg Ala 485 490 495 Asp Ala Met Ala Lys Asp Arg Ser Glu Glu Glu Arg Thr Thr Glu Ala 500 505 510 Glu Lys Asn Glu Arg Val Gln Lys His Leu Lys Ala Leu Thr Ser Glu 515 520 525 Leu Ala Asn Ala Arg Asp Glu Ser Lys Lys Thr Ala Asn Asp Met Ile 530 535 540 His Ala Glu Asn Met Arg Leu Gly Arg Asp Lys Tyr Lys Thr Leu Arg 545 550 555 560 Gln Ile Arg Gln Gly Asn Thr Lys Gln Arg Ile Asp Glu Phe Glu Ser 565 570 575 Met 96473PRTHomo sapiens 96Met Thr Thr Cys Ser Arg Gln Phe Thr Ser Ser Ser Ser Met Lys Gly 1 5 10 15 Ser Cys Gly Ile Gly Gly Gly Ile Gly Gly Gly Ser Ser Arg Ile Ser 20 25 30 Ser Val Leu Ala Gly Gly Ser Cys Arg Ala Pro Ser Thr Tyr Gly Gly 35 40 45 Gly Leu Ser Val Ser Ser Arg Phe Ser Ser Gly Gly Ala Cys Gly Leu 50 55 60 Gly Gly Gly Tyr Gly Gly Gly Phe Ser Ser Ser Ser Ser Phe Gly Ser 65 70 75 80 Gly Phe Gly Gly Gly Tyr Gly Gly Gly Leu Gly Ala Gly Phe Gly Gly 85 90 95 Gly Leu Gly Ala Gly Phe Gly Gly Gly Phe Ala Gly Gly Asp Gly Leu 100 105 110 Leu Val Gly Ser Glu Lys Val Thr Met Gln Asn Leu Asn Asp Arg Leu 115 120 125 Ala Ser Tyr Leu Asp Lys Val Arg Ala Leu Glu Glu Ala Asn Ala Asp 130 135 140 Leu Glu Val Lys Ile Arg Asp Trp Tyr Gln Arg Gln Arg Pro Ser Glu 145 150 155 160 Ile Lys Asp Tyr Ser Pro Tyr Phe Lys Thr Ile Glu Asp Leu Arg Asn 165 170 175 Lys Ile Ile Ala Ala Thr Ile Glu Asn Ala Gln Pro Ile Leu Gln Ile 180 185 190 Asp Asn Ala Arg Leu Ala Ala Asp Asp Phe Arg Thr Lys Tyr Glu His 195 200 205 Glu Leu Ala Leu Arg Gln Thr Val Glu Ala Asp Val Asn Gly Leu Arg 210 215 220 Arg Val Leu Asp Glu Leu Thr Leu Ala Arg Thr Asp Leu Glu Met Gln 225 230 235 240 Ile Glu Gly Leu Lys Glu Glu Leu Ala Tyr Leu Arg Lys Asn His Glu 245 250 255 Glu Glu Met Leu Ala Leu Arg Gly Gln Thr Gly Gly Asp Val Asn Val 260 265 270 Glu Met Asp Ala Ala Pro Gly Val Asp Leu Ser Arg Ile Leu Asn Glu 275 280 285 Met Arg Asp Gln Tyr Glu Gln Met Ala Glu Lys Asn Arg Arg Asp Ala 290 295 300 Glu Thr Trp Phe Leu Ser Lys Thr Glu Glu Leu Asn Lys Glu Val Ala 305 310 315 320 Ser Asn Ser Glu Leu Val Gln Ser Ser Arg Ser Glu Val Thr Glu Leu 325 330 335 Arg Arg Val Leu Gln Gly Leu Glu Ile Glu Leu Gln Ser Gln Leu Ser 340 345 350 Met Lys Ala Ser Leu Glu Asn Ser Leu Glu Glu Thr Lys Gly Arg Tyr 355 360 365 Cys Met Gln Leu Ser Gln Ile Gln Gly Leu Ile Gly Ser Val Glu Glu 370 375 380 Gln Leu Ala Gln Leu Arg Cys Glu Met Glu Gln Gln Ser Gln Glu Tyr 385 390 395 400 Gln Ile Leu Leu Asp Val Lys Thr Arg Leu Glu Gln Glu Ile Ala Thr 405 410 415 Tyr Arg Arg Leu Leu Glu Gly Glu Asp Ala His Leu Ser Ser Gln Gln 420 425 430 Ala Ser Gly Gln Ser Tyr Ser Ser Arg Glu Val Phe Thr Ser Ser Ser 435 440 445 Ser Ser Ser Ser Arg Gln Thr Arg Pro Ile Leu Lys Glu Gln Ser Ser 450 455 460 Ser Ser Phe Ser Gln Gly Gln Ser Ser 465 470 97254PRTHomo sapiens 97Met Ala Ala Tyr Lys Leu Val Leu Ile Arg His Gly Glu Ser Ala Trp 1 5 10 15 Asn Leu Glu Asn Arg Phe Ser Gly Trp Tyr Asp Ala Asp Leu Ser Pro 20 25 30 Ala Gly His Glu Glu Ala Lys Arg Gly Gly Gln Ala Leu Arg Asp Ala 35 40 45 Gly Tyr Glu Phe Asp Ile Cys Phe Thr Ser Val Gln Lys Arg Ala Ile 50 55 60 Arg Thr Leu Trp Thr Val Leu Asp Ala Ile Asp Gln Met Trp Leu Pro 65 70 75 80 Val Val Arg Thr Trp Arg Leu Asn Glu Arg His Tyr Gly Gly Leu Thr 85 90 95 Gly Leu Asn Lys Ala Glu Thr Ala Ala Lys His Gly Glu Ala Gln Val 100 105 110 Lys Ile Trp Arg Arg Ser Tyr Asp Val Pro Pro Pro Pro Met Glu Pro 115 120 125 Asp His Pro Phe Tyr Ser Asn Ile Ser Lys Asp Arg Arg Tyr Ala Asp 130 135 140 Leu Thr Glu Asp Gln Leu Pro Ser Cys Glu Ser Leu Lys Asp Thr Ile 145 150 155 160 Ala Arg Ala Leu Pro Phe Trp Asn Glu Glu Ile Val Pro Gln Ile Lys 165 170 175 Glu Gly Lys Arg Val Leu Ile Ala Ala His Gly Asn Ser Leu Arg Gly 180 185 190 Ile Val Lys His Leu Glu Gly Leu Ser Glu Glu Ala Ile Met Glu Leu 195 200 205 Asn Leu Pro Thr Gly Ile Pro Ile Val Tyr Glu Leu Asp Lys Asn Leu 210 215 220 Lys Pro Ile Lys Pro Met Gln Phe Leu Gly Asp Glu Glu Thr Val Arg 225 230 235 240 Lys Ala Met Glu Ala Val Ala Ala Gln Gly Lys Ala Lys Lys 245 250 98505PRTHomo sapiens 98Met Arg Leu Arg Arg Leu Ala Leu Phe Pro Gly Val Ala Leu Leu Leu 1 5 10 15 Ala Ala Ala Arg Leu Ala Ala Ala Ser Asp Val Leu Glu Leu Thr Asp 20 25 30 Asp Asn Phe Glu Ser Arg Ile Ser Asp Thr Gly Ser Ala Gly Leu Met 35 40 45 Leu Val Glu Phe Phe Ala Pro Trp Cys Gly His Cys Lys Arg Leu Ala 50 55 60 Pro Glu Tyr Glu Ala Ala Ala Thr Arg Leu Lys Gly Ile Val Pro Leu 65 70 75 80 Ala Lys Val Asp Cys Thr Ala Asn Thr Asn Thr Cys Asn Lys Tyr Gly 85 90 95 Val Ser Gly Tyr Pro Thr Leu Lys Ile Phe Arg Asp Gly Glu Glu Ala 100 105 110 Gly Ala Tyr Asp Gly Pro Arg Thr Ala Asp Gly Ile Val Ser His Leu 115 120 125 Lys Lys Gln Ala Gly Pro Ala Ser Val Pro Leu Arg Thr Glu Glu Glu 130 135 140 Phe Lys Lys Phe Ile Ser Asp Lys Asp Ala Ser Ile Val Gly Phe Phe 145 150 155 160 Asp Asp Ser Phe Ser Glu Ala His Ser Glu Phe Leu Lys Ala Ala Ser 165 170 175 Asn Leu Arg Asp Asn Tyr Arg Phe Ala His Thr Asn Val Glu Ser Leu 180 185 190 Val Asn Glu Tyr Asp Asp Asn Gly Glu Gly Ile Ile Leu Phe Arg Pro 195 200 205 Ser His Leu Thr Asn Lys Phe Glu Asp Lys Thr Val Ala Tyr Thr Glu 210 215 220 Gln Lys Met Thr Ser Gly Lys Ile Lys Lys Phe Ile Gln Glu Asn Ile 225 230 235 240 Phe Gly Ile Cys Pro His Met Thr Glu Asp Asn Lys Asp Leu Ile Gln 245 250 255 Gly Lys Asp Leu Leu Ile Ala Tyr Tyr Asp Val Asp Tyr Glu Lys Asn 260 265 270 Ala Lys Gly Ser Asn Tyr Trp Arg Asn Arg Val Met Met Val Ala Lys 275 280 285 Lys Phe Leu Asp Ala Gly His Lys Leu Asn Phe Ala Val Ala Ser Arg 290 295 300 Lys Thr Phe Ser His Glu Leu Ser Asp Phe Gly Leu Glu Ser Thr Ala 305 310 315 320 Gly Glu Ile Pro Val Val Ala Ile Arg Thr Ala Lys Gly Glu Lys Phe 325 330 335 Val Met Gln Glu Glu Phe Ser Arg Asp Gly Lys Ala Leu Glu Arg Phe 340 345 350 Leu Gln Asp Tyr Phe Asp Gly Asn Leu Lys Arg Tyr Leu Lys Ser Glu 355 360 365 Pro Ile Pro Glu Ser Asn Asp Gly Pro Val Lys Val Val Val Ala Glu 370 375 380 Asn Phe Asp Glu Ile Val Asn Asn Glu Asn Lys Asp Val Leu Ile Glu 385 390 395 400 Phe Tyr Ala Pro Trp Cys Gly His Cys Lys Asn Leu Glu Pro Lys Tyr 405 410 415 Lys Glu Leu Gly Glu Lys Leu Ser Lys Asp Pro Asn Ile Val Ile Ala 420 425 430 Lys Met Asp Ala Thr Ala Asn Asp Val Pro Ser Pro Tyr Glu Val Arg 435 440 445 Gly Phe Pro Thr Ile Tyr Phe Ser Pro Ala Asn Lys Lys Leu Asn Pro 450 455 460 Lys Lys Tyr Glu Gly Gly Arg Glu Leu Ser Asp Phe Ile Ser Tyr Leu 465 470 475 480 Gln Arg Glu Ala Thr Asn Pro Pro Val Ile Gln Glu Glu Lys Pro Lys 485 490 495 Lys Lys Lys Lys Ala Gln Glu Asp Leu 500 505 99216PRTHomo sapiens 99Met Leu Arg Leu Ser Glu Arg Asn Met Lys Val Leu Leu Ala Ala Ala 1 5 10 15 Leu Ile Ala Gly Ser Val Phe Phe Leu Leu Leu Pro Gly Pro Ser Ala 20 25 30 Ala Asp Glu Lys Lys Lys Gly Pro Lys Val Thr Val Lys Val Tyr Phe 35 40 45 Asp Leu Arg Ile Gly Asp Glu Asp Val Gly Arg Val Ile Phe Gly Leu 50 55 60 Phe Gly Lys Thr Val Pro Lys Thr Val Asp Asn Phe Val Ala Leu Ala 65 70 75 80 Thr Gly Glu Lys Gly Phe Gly Tyr Lys Asn Ser Lys Phe His Arg Val 85 90 95 Ile Lys Asp Phe Met Ile Gln Gly Gly Asp Phe Thr Arg Gly Asp Gly 100 105 110 Thr Gly Gly Lys Ser Ile Tyr Gly Glu Arg Phe Pro Asp Glu Asn Phe 115 120 125 Lys Leu Lys His Tyr Gly Pro Gly Trp Val Ser Met Ala Asn Ala Gly 130 135 140 Lys Asp Thr Asn Gly Ser Gln Phe Phe Ile Thr Thr Val Lys Thr Ala 145 150 155 160 Trp Leu Asp Gly Lys His Val Val Phe Gly Lys Val Leu Glu Gly Met 165 170 175 Glu Val Val Arg Lys Val Glu Ser Thr Lys Thr Asp Ser Arg Asp Lys 180 185 190 Pro Leu Lys Asp Val Ile Ile Ala Asp Cys Gly Lys Ile Glu Val Glu 195 200 205 Lys Pro Phe Ala Ile Ala Lys Glu 210 215 100136PRTHomo sapiens 100Met Ser Asn Val Pro His Lys Ser Ser Leu Pro Glu Gly Ile Arg Pro 1 5 10 15 Gly Thr Val Leu Arg Ile Arg Gly Leu Val Pro Pro Asn Ala Ser Arg 20 25 30 Phe His Val Asn Leu Leu Cys Gly Glu Glu Gln Gly Ser Asp Ala Ala 35 40 45 Leu His Phe Asn Pro Arg Leu Asp Thr Ser Glu Val Val Phe Asn Ser 50 55 60 Lys Glu Gln Gly Ser Trp Gly Arg Glu Glu Arg Gly Pro Gly Val Pro 65 70 75 80 Phe Gln Arg Gly Gln Pro Phe Glu Val Leu Ile Ile Ala Ser Asp Asp 85 90 95 Gly Phe Lys Ala Val Val Gly Asp Ala Gln Tyr His His Phe Arg His 100 105 110 Arg Leu Pro Leu Ala Arg Val Arg Leu Val Glu Val Gly Gly Asp Val 115 120 125 Gln Leu Asp Ser Val Arg Ile Phe 130 135 101602PRTHomo sapiens 101Met Val Lys Leu Ala Lys Ala Gly Lys Asn Gln Gly Asp Pro Lys Lys 1 5 10 15 Met Ala Pro Pro Pro Lys Glu Val Glu Glu Asp Ser Glu Asp Glu Glu 20 25 30 Met Ser Glu Asp Glu Glu Asp Asp Ser Ser Gly Glu Glu Leu Asn Asp 35 40 45 Asp Phe Tyr Gln Thr Thr Met His Thr Leu Trp Lys Lys Gly Lys Lys 50 55 60 Ala Ala Ala Thr Ser Ala Ile Pro Ala Lys Gly Ala Lys Asn Gly Lys 65 70 75 80 Asn Ala Lys Lys Glu Asp Ser Asp Glu Glu Glu Asp Asp Asp Ser Glu 85 90 95 Glu Asp Glu Glu Asp Asp Glu Asp Glu Asp Glu Asp Glu Asp Glu Ile 100 105 110 Glu Pro Ala Ala Met Lys Ala Ala Ala Ala Ala Pro Ala Ser Glu Asp 115 120 125 Glu Asp Asp Glu Asp Asp Glu Asp Asp Glu Asp Asp Asp Asp Asp Glu 130 135 140 Glu Asp Asp Asp Asp Asp Glu Asp Asp Glu Glu Glu Glu Glu Glu Glu 145 150 155 160 Glu Glu Glu Pro Val Lys Glu Ala Pro Gly Lys Arg Lys Lys Glu Met 165 170 175 Ala Lys Gln Lys Ala Ala Pro Glu Ala Lys Lys Gln Lys Val Glu Gly 180 185 190 Thr Glu Pro Thr Thr Ala Phe Asn Leu Phe Val Gly Asn Leu Asn Phe 195 200 205 Asn Lys Ser Ala Pro Glu Leu Lys Thr Gly Ile Ser Asp Val Phe Ala 210 215 220 Lys Asn Asp Leu Ala Val Val Asp Val Arg Ile Gly Met Thr Arg Lys 225 230 235 240 Phe Gly Tyr Val Asp Phe Glu Ser Ala Glu Asp Leu Glu Lys Ala Leu 245 250 255 Glu Leu Thr Gly Leu Lys Val Phe Gly Asn Glu Ile Lys Leu Glu Lys 260 265 270 Pro Lys Gly Lys Asp Ser Lys Lys Glu Arg Asp Ala Arg Thr Leu Leu 275 280 285 Ala Lys Asn Leu Pro Tyr Lys Val Thr Gln Asp Glu Leu Lys Glu Val 290 295 300 Phe Glu Asp Ala Ala Glu Ile Arg Leu Val Ser Lys Asp Gly Lys Ser 305 310 315 320 Lys Gly Ile Ala Tyr Ile Glu Phe Lys Thr Glu Ala Asp Ala Glu Lys 325 330 335 Thr Phe Glu Glu Lys Gln Gly Thr Glu Ile Asp Gly Arg Ser Ile Ser 340 345 350 Leu Tyr Tyr Thr Gly Glu Lys Gly Gln Asn Gln Asp Tyr Arg Gly Gly 355 360 365 Lys Asn Ser Thr Trp Ser Gly Glu Ser Lys Thr Leu Val Leu Ser Asn 370 375 380 Leu Ser Tyr Ser Ala Thr Glu Glu Thr Leu Gln Glu Val Phe Glu Lys 385 390 395 400 Ala Thr Phe Ile Lys Val Pro Gln Asn Gln Asn Gly Lys Ser Lys Gly 405 410 415 Tyr Ala Phe Ile Glu Phe Ala Ser Phe Glu Asp Ala Lys Glu Ala Leu 420 425 430 Asn Ser Cys Asn Lys Arg Glu Ile Glu Gly Arg Ala Ile Arg Leu Glu 435 440 445 Leu Gln Gly Pro Arg Gly Ser Pro Asn Ala Arg Ser Gln Pro Ser Lys 450 455 460 Thr Leu Phe Val Lys Gly Leu Ser Glu Asp Thr Thr Glu Glu Thr Leu 465 470 475 480 Lys Glu Ser Phe Asp Gly Ser Val Arg Ala Arg Ile Val Thr Asp Arg

485 490 495 Glu Thr Gly Ser Ser Lys Gly Phe Gly Phe Val Asp Phe Asn Ser Glu 500 505 510 Glu Asp Ala Lys Ala Ala Lys Glu Ala Met Glu Asp Gly Glu Ile Asp 515 520 525 Gly Asn Lys Val Thr Leu Asp Trp Ala Lys Pro Lys Gly Glu Gly Gly 530 535 540 Phe Gly Gly Arg Gly Gly Gly Arg Gly Gly Phe Gly Gly Arg Gly Gly 545 550 555 560 Gly Arg Gly Gly Arg Gly Gly Phe Gly Gly Arg Gly Arg Gly Gly Phe 565 570 575 Gly Gly Arg Gly Gly Phe Arg Gly Gly Arg Gly Gly Gly Gly Asp His 580 585 590 Lys Pro Gln Gly Lys Lys Thr Lys Phe Glu 595 600 102198PRTHomo sapiens 102Met Ala Ser Gly Asn Ala Arg Ile Gly Lys Pro Ala Pro Asp Phe Lys 1 5 10 15 Ala Thr Ala Val Val Asp Gly Ala Phe Lys Glu Val Lys Leu Ser Asp 20 25 30 Tyr Lys Gly Lys Tyr Val Val Leu Phe Phe Tyr Pro Leu Asp Phe Thr 35 40 45 Phe Val Cys Pro Thr Glu Ile Ile Ala Phe Ser Asn Arg Ala Glu Asp 50 55 60 Phe Arg Lys Leu Gly Cys Glu Val Leu Gly Val Ser Val Asp Ser Gln 65 70 75 80 Phe Thr His Leu Ala Trp Ile Asn Thr Pro Arg Lys Glu Gly Gly Leu 85 90 95 Gly Pro Leu Asn Ile Pro Leu Leu Ala Asp Val Thr Arg Arg Leu Ser 100 105 110 Glu Asp Tyr Gly Val Leu Lys Thr Asp Glu Gly Ile Ala Tyr Arg Gly 115 120 125 Leu Phe Ile Ile Asp Gly Lys Gly Val Leu Arg Gln Ile Thr Val Asn 130 135 140 Asp Leu Pro Val Gly Arg Ser Val Asp Glu Ala Leu Arg Leu Val Gln 145 150 155 160 Ala Phe Gln Tyr Thr Asp Glu His Gly Glu Val Cys Pro Ala Gly Trp 165 170 175 Lys Pro Gly Ser Asp Thr Ile Lys Pro Asn Val Asp Asp Ser Lys Glu 180 185 190 Tyr Phe Ser Lys His Asn 195 1038PRTHomo sapiens 103Gly Thr Leu Asp Pro Val Glu Lys 1 5 10418PRTHomo sapiens 104Thr Val Thr Asn Ala Val Val Thr Val Pro Ala Tyr Phe Asn Asp Ser 1 5 10 15 Gln Arg 10511PRTHomo sapiens 105Ala Leu Asn Ser Ile Ile Asp Val Tyr His Lys 1 5 10 10613PRTHomo sapiens 106Leu Gly His Pro Asp Thr Leu Asn Gln Gly Glu Phe Lys 1 5 10 10715PRTHomo sapiens 107Asn Ile Glu Thr Ile Ile Asn Thr Phe His Gln Tyr Ser Val Lys 1 5 10 15 1087PRTHomo sapiens 108Glu Thr Ile Glu Gln Glu Lys 1 5

Claims

1-36. (canceled)

37. An in vitro method for determining the sensitizing potential of a test compound, comprising the steps of (a) contacting said test compound with a cell; (b) determining the presence or a change in the level of expression of a plurality of marker proteins selected from Table 1, Table 1 (A) Group 1; Table 1 (B) Group 2; or Table 1 (C) Group 3 or a combination thereof, in said cell; and (c) determining the sensitizing potential of said test compound based on said presence or change in level of expression wherein a change in the presence or level of expression of said one or more marker proteins is indicative of said test compound having sensitizing potential; wherein said cell is selected from the group consisting of a cell representative of a mammalian skin cell; a primary keratinocyte, a keratinocyte derived cell line, an epidermal keratinocyte, a bulge-derived keratinocyte, a foreskin keratinocytes, a human cell having keratinocyte properties, a cell derived from HaCaT cell line and a cell derived from NCTC2544 cell line.

38. A method according to claim 37 wherein said plurality of marker proteins are selected from Table 1 (A) Group 1.

39. A method according to claim 37 wherein said plurality of marker proteins are selected from Table 1 (B) Group 2.

40. A method according to claim 37 wherein step (b) includes comparing the presence or level of expression of the plurality of protein markers with a reference level.

41. A method according to claim 37 wherein step (b) includes contacting the cell with a plurality of specific binding members that each selectively bind to one of said plurality of marker proteins or nucleic acid sequences encoding said marker proteins; and detecting and/or quantifying a complex formed by said specific binding member and the marker protein or nucleic acid sequence encoding said marker protein.

42. A method according to claim 37 wherein said determination step includes preparing a standard curve using standards of known expression levels of the plurality of marker proteins and comparing the reading obtained with the cell contacted with the test compound so as to derive a measure of the change in level of expression of the plurality of marker proteins.

43. A method according to claim 41 wherein said specific binding member is an antibody or fragment thereof that specifically and selectively binds to said marker protein.

44. A method according to claim 43 wherein said specific binding member is an auto-antibody or fragment thereof that specifically and selectively binds to said marker protein and wherein said auto-antibody is prepared from a blood sample obtained from a patient with skin irritation or allergy.

45. A method according to claim 41 wherein said specific binding member is an aptamer.

46. A method according to claim 37 wherein step (b) is performed by mass spectrometry.

47. A method according to claim 37 wherein step (b) is performed by Selected Reaction Monitoring using one or more transitions for protein marker derived peptides; (i) comparing the peptide levels in the cell under test with peptide levels previously determined to represent sensitivity of the cell, and (ii) determining the sensitizing potential of the test compound based on changes in expression of said plurality of marker proteins.

48. A method according to claim 47 wherein step (i) includes determining the amount of marker protein derived peptides from the cell under test with known amounts of corresponding synthetic peptides, wherein the synthetic peptides are identical in sequence to the peptides obtained from the cell except for a label.

49. A method according to claim 48 wherein the label is a tag of a different mass or a heavy isotope.

50. A method according to claim 47 wherein the one or more transitions for the protein marker derived peptides comprise one or more transitions from Table 5.

51. A method according to claim 37 wherein step (b) comprises determining the presence or amount of mRNA encoding said plurality of marker proteins in the cell following contact with the test compound.

52. A method according to claim 51 wherein the presence or amount of mRNA is determined using a primer or probe which selectively binds to the sequence of the protein marker encoding gene or complement thereof.

53. A kit for use in determining the sensitizing potential of a test compound in vitro, said kit allowing the user to determine the presence or level of expression of an analyte selected from a plurality of marker proteins or fragments thereof provided in Table 1, a plurality of antibodies against said marker proteins and a plurality of nucleic acid molecules encoding said marker proteins or fragments thereof, in a cell under test; the kit comprising (a) a solid support having a plurality of binding members each capable of binding to an analyte immobilised thereon; (b) a developing agent comprising a label; and, optionally (c) one or more components selected from the group consisting of washing solutions, diluents and buffers.

54. A kit according to claim 53 wherein the plurality of binding members are antibodies each capable of selectively binding to a marker protein selected from Table 1, Table 1 (A) Group 1; Table 1 (B) Group 2; or Table 1 (C) Group 3 or a combination thereof.

55. A kit according to claim 53 wherein the plurality of binding members are nucleic acid sequences each capable of selectively binding to a nucleic acid encoding said marker protein.

56. A kit for use in determining the sensitizing potential of a test compound in vitro, said kit allowing the user to determine the presence or level of expression of a plurality of marker proteins or fragments thereof provided in Table 1, in a cell under test; the kit comprising (a) a set of reference peptides in an assay compatible format wherein each peptide in the set is uniquely representative of each of the plurality of marker proteins provided in Table 1, Table 1 (A) Group 1; Table 1 (B) Group 2; or Table 1 (c) Group 3 or a combination thereof; and, optionally (b) one or more components selected from the group consisting of washing solutions, diluents and buffers.

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